Identification

Name
Palbociclib
Accession Number
DB09073
Type
Small Molecule
Groups
Approved, Investigational
Description

Palbociclib is an oral, reversible, selective, small-molecule inhibitor of CDK4 and CDK6 indicated in combination with letrozole for the treatment of postmenopausal women with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer as initial endocrine-based therapy for their metastatic disease. CDK4 and CDK6 along with their regulatory partner cyclin D1 play a key role in regulating the G1- to S-phase cell-cycle transition via regulation of phosphorylation of the retinoblastoma (Rb) protein. Inhibition of these proteins leads to reduced phosphorylation of Rb, inhibition of downstream signalling, and increased tumor growth arrest. Palbociclib received an accelerated approval from the Food and Drug Administration on February 3, 2015.

Structure
Thumb
Synonyms
  • 6-acetyl-8-cyclopentyl-5-methyl-2-{[5-(piperazin-1-yl)pyridin-2-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one
  • Palbociclib
External IDs
PD 0332991 / PD 332991 / PD-0332991 / PD-332991 / PD0332991 / PD332991
Product Ingredients
IngredientUNIICASInChI Key
Palbociclib IsethionateW1NYL2IRDR827022-33-3LYYVFHRFIJKPOV-UHFFFAOYSA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
IbranceCapsule125 mg/1OralPfizer Laboratories Div Pfizer Inc2015-02-03Not applicableUs
IbranceCapsule75 mgOralPfizer2016-04-20Not applicableCanada
IbranceCapsule125 mgOralPfizer2016-04-19Not applicableCanada
IbranceCapsule75 mg/1OralPfizer Laboratories Div Pfizer Inc2015-02-03Not applicableUs
IbranceCapsule100 mgOralPfizer2016-04-19Not applicableCanada
IbranceCapsule125 mg/1OralU.S. Pharmaceuticals2015-02-03Not applicableUs
IbranceCapsule100 mg/1OralPfizer Laboratories Div Pfizer Inc2015-02-03Not applicableUs
Categories
UNII
G9ZF61LE7G
CAS number
571190-30-2
Weight
Average: 447.5328
Monoisotopic: 447.238273207
Chemical Formula
C24H29N7O2
InChI Key
AHJRHEGDXFFMBM-UHFFFAOYSA-N
InChI
InChI=1S/C24H29N7O2/c1-15-19-14-27-24(28-20-8-7-18(13-26-20)30-11-9-25-10-12-30)29-22(19)31(17-5-3-4-6-17)23(33)21(15)16(2)32/h7-8,13-14,17,25H,3-6,9-12H2,1-2H3,(H,26,27,28,29)
IUPAC Name
6-acetyl-8-cyclopentyl-5-methyl-2-{[5-(piperazin-1-yl)pyridin-2-yl]amino}-7H,8H-pyrido[2,3-d]pyrimidin-7-one
SMILES
CC(=O)C1=C(C)C2=CN=C(NC3=NC=C(C=C3)N3CCNCC3)N=C2N(C2CCCC2)C1=O

Pharmacology

Indication

Palbociclib is indicated in combination with letrozole for the treatment of postmenopausal women with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer as initial endocrine-based therapy for their metastatic disease. This indication is approved under accelerated approval based on progression-free survival (PFS). Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

Associated Conditions
Pharmacodynamics

Treatment of breast cancer cell lines with the combination of palbociclib and antiestrogens leads to decreased retinoblastoma protein (Rb) phosphorylation resulting in reduced E2F expression and signaling and increased growth arrest compared to treatment with each drug alone. In vitro treatment of ER-positive breast cancer cell lines with the combination of palbociclib and antiestrogens leads to increased cell senescence, which was sustained for up to 6 days following drug removal. In vivo studies using a patient-derived ER-positive breast cancer xenograft model demonstrated that the combination of palbociclib and letrozole increased the inhibition of Rb phosphorylation, downstream signaling and tumor growth compared to each drug alone.

Mechanism of action

Palbociclib is an oral, reversible, selective, small-molecule inhibitor of CDK4 and CDK6. CDK4 and CDK6 along with their regulatory partner cyclin D1 play a key role in regulating the G1- to S-phase cell-cycle transition via regulation of phosphorylation of the retinoblastoma (Rb) protein.

TargetActionsOrganism
ACyclin-dependent kinase 4
inhibitor
Human
ACyclin-dependent kinase 6
inhibitor
Human
Absorption

The mean Cmax of palbociclib is generally observed between 6 to 12 hours (time to reach maximum concentration, Tmax) following oral administration. The mean absolute bioavailability after an oral 125 mg dose is 46%.

Volume of distribution

The mean apparent distribution of palbociclib is 2583 L, suggesting that palbociclib penetrates extensively into peripheral tissues.

Protein binding

Binding of palbociclib to human plasma proteins in vitro is approximately 85%.

Metabolism

The primary metabolic pathways for palbociclib involve oxidation and sulfonation, with acylation and glucuronidation contributing as minor pathways. Palbociclib is the major circulating drug-derived entity in plasma (23%). The major circulating metabolite was found to be a glucuronide conjugate of palbociclib, although it only represented 1.5% of the administered dose in the excreta.

Route of elimination

Palbociclib was extensively metabolized with unchanged drug accounting for 2.3% and 6.9% of radioactivity in feces and urine, respectively. In feces, the sulfamic acid conjugate of palbociclib was the major drug-related component, accounting for 26% of the administered dose.

Half life

The mean plasma elimination half-life is 29 hours.

Clearance

63.1 L/hr

Toxicity
Not Available
Affected organisms
Not Available
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe serum concentration of (R)-warfarin can be increased when it is combined with Palbociclib.
(S)-WarfarinThe serum concentration of (S)-Warfarin can be increased when it is combined with Palbociclib.
2-MethoxyethanolThe risk or severity of adverse effects can be increased when 2-Methoxyethanol is combined with Palbociclib.
3,5-diiodothyropropionic acidThe metabolism of 3,5-diiodothyropropionic acid can be decreased when combined with Palbociclib.
4-hydroxycoumarinThe metabolism of 4-hydroxycoumarin can be decreased when combined with Palbociclib.
5-androstenedioneThe metabolism of 5-androstenedione can be decreased when combined with Palbociclib.
6-Deoxyerythronolide BThe metabolism of Palbociclib can be decreased when combined with 6-Deoxyerythronolide B.
6-O-benzylguanineThe metabolism of 6-O-benzylguanine can be decreased when combined with Palbociclib.
7-ethyl-10-hydroxycamptothecinThe metabolism of Palbociclib can be decreased when combined with 7-ethyl-10-hydroxycamptothecin.
9-(N-methyl-L-isoleucine)-cyclosporin AThe risk or severity of adverse effects can be increased when Palbociclib is combined with 9-(N-methyl-L-isoleucine)-cyclosporin A.
Food Interactions
Not Available

References

General References
  1. Dhillon S: Palbociclib: first global approval. Drugs. 2015 Apr;75(5):543-51. doi: 10.1007/s40265-015-0379-9. [PubMed:25792301]
  2. Fry DW, Harvey PJ, Keller PR, Elliott WL, Meade M, Trachet E, Albassam M, Zheng X, Leopold WR, Pryer NK, Toogood PL: Specific inhibition of cyclin-dependent kinase 4/6 by PD 0332991 and associated antitumor activity in human tumor xenografts. Mol Cancer Ther. 2004 Nov;3(11):1427-38. [PubMed:15542782]
  3. Logan JE, Mostofizadeh N, Desai AJ, VON Euw E, Conklin D, Konkankit V, Hamidi H, Eckardt M, Anderson L, Chen HW, Ginther C, Taschereau E, Bui PH, Christensen JG, Belldegrun AS, Slamon DJ, Kabbinavar FF: PD-0332991, a potent and selective inhibitor of cyclin-dependent kinase 4/6, demonstrates inhibition of proliferation in renal cell carcinoma at nanomolar concentrations and molecular markers predict for sensitivity. Anticancer Res. 2013 Aug;33(8):2997-3004. [PubMed:23898052]
  4. Authors unspecified: Palbociclib Extends Survival in Advanced Breast Cancer. Cancer Discov. 2015 Jul;5(7):OF5. doi: 10.1158/2159-8290.CD-NB2015-083. Epub 2015 Jun 2. [PubMed:26036642]
  5. Turner NC, Ro J, Andre F, Loi S, Verma S, Iwata H, Harbeck N, Loibl S, Huang Bartlett C, Zhang K, Giorgetti C, Randolph S, Koehler M, Cristofanilli M: Palbociclib in Hormone-Receptor-Positive Advanced Breast Cancer. N Engl J Med. 2015 Jul 16;373(3):209-19. doi: 10.1056/NEJMoa1505270. Epub 2015 Jun 1. [PubMed:26030518]
  6. Finn RS, Crown JP, Lang I, Boer K, Bondarenko IM, Kulyk SO, Ettl J, Patel R, Pinter T, Schmidt M, Shparyk Y, Thummala AR, Voytko NL, Fowst C, Huang X, Kim ST, Randolph S, Slamon DJ: The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study. Lancet Oncol. 2015 Jan;16(1):25-35. doi: 10.1016/S1470-2045(14)71159-3. Epub 2014 Dec 16. [PubMed:25524798]
  7. DeMichele A, Clark AS, Tan KS, Heitjan DF, Gramlich K, Gallagher M, Lal P, Feldman M, Zhang P, Colameco C, Lewis D, Langer M, Goodman N, Domchek S, Gogineni K, Rosen M, Fox K, O'Dwyer P: CDK 4/6 inhibitor palbociclib (PD0332991) in Rb+ advanced breast cancer: phase II activity, safety, and predictive biomarker assessment. Clin Cancer Res. 2015 Mar 1;21(5):995-1001. doi: 10.1158/1078-0432.CCR-14-2258. Epub 2014 Dec 11. [PubMed:25501126]
External Links
KEGG Drug
D10372
PubChem Compound
5330286
PubChem Substance
310265004
ChemSpider
4487437
BindingDB
6309
ChEBI
85993
ChEMBL
CHEMBL189963
PharmGKB
PA166153469
HET
LQQ
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Palbociclib
ATC Codes
L01XE33 — Palbociclib
AHFS Codes
  • 10:00.00 — Antineoplastic Agents
PDB Entries
2euf / 5l2i
FDA label
Download (481 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1Active Not RecruitingOtherAdvanced Breast Cancer1
1Active Not RecruitingTreatmentAdvanced Solid Tumor Malignancies1
1Active Not RecruitingTreatmentCCND1 Positive / Recurrent Mantle Cell Lymphoma / T(11;14)1
1Active Not RecruitingTreatmentCancer, Breast1
1Active Not RecruitingTreatmentMantle Cell Lymphoma (MCL)1
1CompletedBasic ScienceHealthy Volunteers11
1CompletedBasic ScienceHealthy, Hepatic Insufficiency1
1CompletedBasic ScienceImpaired Renal Function1
1CompletedTreatmentMalignancies1
1CompletedTreatmentMantle Cell Lymphoma (MCL)1
1CompletedTreatmentNeoplasms / Non-Hodgkin's Lymphoma (NHL)1
1Not Yet RecruitingTreatmentAdvanced Breast Cancer / BRCA1 Mutations / BRCA2 Mutation / Locally Advanced Breast Cancer (LABC) / Metastatic Breast Cancer (MBC)1
1Not Yet RecruitingTreatmentEwing's Sarcoma (ES) / Medulloblastomas / Neuroblastomas / Rhabdoid Tumors / Rhabdomyosarcomas / Tumors, Solid1
1RecruitingTreatmentAcute Lymphoblastic Leukaemias (ALL) / Hematopoietic/Lymphoid Cancer / Leukemia Acute Myeloid Leukemia (AML)1
1RecruitingTreatmentAcute Lymphoblastic Leukemia With Failed Remission / Acute Lymphoblastic Leukemia, in Relapse1
1RecruitingTreatmentAdvanced Breast Cancer1
1RecruitingTreatmentAdvanced Solid Tumours / Cancer, Breast1
1RecruitingTreatmentBladder Cancers / Cancer of the Ovary / Cancer of Unknown Primary / Colorectal Cancers / Head and Neck Carcinoma / Sarcomas / Solid Neoplasms / Stage III Pancreatic Cancer / Stage IIIA Breast Cancer / Stage IIIA Non-Small Cell Lung Cancer / Stage IIIB Breast Cancer / Stage IIIb Non-small Cell Lung Cancer / Stage IIIC Breast Cancer / Stage IV Breast Cancer / Stage IV Non-Small Cell Lung Cancer / Stage IVA Pancreatic Cancer / Stage IVB Pancreatic Cancer1
1RecruitingTreatmentCancer, Breast5
1RecruitingTreatmentCancer, Breast / Tumors, Solid1
1RecruitingTreatmentCastration Resistant Prostate Cancer (CRPC) / Hormone Receptor Positive Advanced Breast Cancer / Human Epidermal Receptor 2 Negative Advanced Breast Cancer / Metastatic Breast Cancer (MBC)1
1RecruitingTreatmentChildhood Choroid Plexus Tumor / Childhood Ependymoblastoma / Childhood Grade III Meningioma / Childhood High-grade Cerebellar Astrocytoma / Childhood High-grade Cerebral Astrocytoma / Childhood Medulloepithelioma / Recurrent Childhood Anaplastic Astrocytoma / Recurrent Childhood Anaplastic Oligoastrocytoma / Recurrent Childhood Anaplastic Oligodendroglioma / Recurrent Childhood Brain Stem Glioma / Recurrent Childhood Cerebellar Astrocytoma / Recurrent Childhood Cerebral Astrocytoma / Recurrent Childhood Giant Cell Glioblastoma / Recurrent Childhood Glioblastoma / Recurrent Childhood Gliomatosis Cerebri / Recurrent Childhood Gliosarcoma / Recurrent Childhood Medulloblastoma / Recurrent Childhood Pineoblastoma / Recurrent Childhood Supratentorial Primitive Neuroectodermal Tumor1
1RecruitingTreatmentHead & Neck Cancer / Lung Cancer Squamous Cell / Malignant Neoplasm of Pancreas / Tumors, Solid1
1RecruitingTreatmentHead and Neck Squamous Cell Carcinoma (HNSCC)1
1RecruitingTreatmentMalignant Neoplasm of Breast / Malignant Neoplasms of Digestive Organs / Malignant Neoplasms of Female Genital Organs / Malignant Neoplasms of Ill-defined Secondary and Unspecified Sites / Malignant Neoplasms of Independent (Primary) Multiple Sites / Malignant Neoplasms of Lip Oral Cavity and Pharynx / Malignant Neoplasms of Mesothelial and Soft Tissue / Malignant Neoplasms of Respiratory and Intrathoracic Organs / Malignant Neoplasms of Thyroid and Other Endocrine Glands / Malignant Neoplasms of Urinary Tract / Neoplasms of Uncertain or Unknown Behavior1
1RecruitingTreatmentMalignant Neoplasm of Pancreas / Tumors, Solid1
1RecruitingTreatmentMetastatic Breast Cancer (MBC)1
1RecruitingTreatmentMetastatic Pancreatic Ductal Adenocarcinoma1
1RecruitingTreatmentRecurrent B Acute Lymphoblastic Leukemia / Refractory B Acute Lymphoblastic Leukemia1
1TerminatedTreatmentAcute, relapsed Leukemia / High-Risk Myelodysplasia / Refractory Acute Leukemia1
1TerminatedTreatmentMultiple Myeloma (MM)1
1, 2Active Not RecruitingTreatmentAdvanced and Metastatic Breast Cancer1
1, 2Active Not RecruitingTreatmentBreast Cancer Metastatic / Metastatic Invasive Breast Cancer / Unresectable Locally Advanced Invasive Breast Cancer1
1, 2Active Not RecruitingTreatmentKRAS Mutant Non-Small Cell Lung Cancer / Tumors, Solid1
1, 2Not Yet RecruitingTreatmentHead and Neck Carcinoma / Locally Advanced / Unresectable1
1, 2RecruitingTreatmentAcute Lymphoblastic Leukaemias (ALL) / Leukemia Acute Myeloid Leukemia (AML)1
1, 2RecruitingTreatmentBreast Cancer Metastatic / Her2-Positive Breast Cancer1
1, 2RecruitingTreatmentBreast Diseases / Neoplasms, Breast1
1, 2RecruitingTreatmentCDNKN2A Loss Defined / Melanoma BRAF V600E/K Mutated1
1, 2RecruitingTreatmentCancer, Breast2
1, 2RecruitingTreatmentCarcinoma, Squamous Cell of Head and Neck1
1, 2RecruitingTreatmentEstrogen Receptor Positive / HER2/Neu Negative / Invasive Breast Carcinoma / Multifocal Breast Carcinoma / One to five years postmenopausal / Progesterone Receptor Positive / Stage I Breast Carcinoma / Stage IA Breast Cancer / Stage IB Breast Cancer / Stage II Breast Cancer / Stage IIA Breast Cancer / Stage IIB Breast Cancer / Stage III Breast Cancer / Stage IIIA Breast Cancer / Stage IIIB Breast Cancer / Stage IIIC Breast Cancer / Stage IV Breast Cancer1
1, 2RecruitingTreatmentGlioblastoma, Adult1
1, 2RecruitingTreatmentHormone Receptor (HR)-Positive Breast Cancer / Human Epidermal Growth Factor 2 Negative Carcinoma of Breast1
1, 2RecruitingTreatmentLung Cancers1
1, 2RecruitingTreatmentMetastatic Breast Cancer (MBC)1
1, 2RecruitingTreatmentMetastatic Non-Small Cell Lung Cancer / Non-Small Cell Lung Cancer Stage IIIB1
2Active Not RecruitingBasic ScienceCancer, Breast1
2Active Not RecruitingOtherNeoplasms, Breast1
2Active Not RecruitingTreatmentAdvanced Gastrointestinal Stromal Tumors1
2Active Not RecruitingTreatmentAdvanced Hepatocellular Carcinoma / HCC / Liver Cancer1
2Active Not RecruitingTreatmentCancer, Breast4
2Active Not RecruitingTreatmentCancer, Breast / Carcinoma, Breast / Tumors, Breast1
2Active Not RecruitingTreatmentLung Cancer Non-Small Cell Cancer (NSCLC)1
2Active Not RecruitingTreatmentMetastatic Breast Cancer (MBC)1
2Active Not RecruitingTreatmentNeoadjuvant Operable Breast Cancer1
2Active Not RecruitingTreatmentOvarian Epithelial Carcinoma1
2Active Not RecruitingTreatmentProstate Cancer1
2Active Not RecruitingTreatmentSquamous Cell Carcinoma of the Head and Neck (SCCHN)1
2CompletedTreatmentCancer, Breast2
2CompletedTreatmentLiposarcoma / Sarcomas1
2CompletedTreatmentLung Cancer Non-Small Cell Cancer (NSCLC)1
2CompletedTreatmentMultiple Myeloma (MM)1
2CompletedTreatmentNeoplasms / Neoplasms, Breast1
2CompletedTreatmentPancreatic Neuroendocrine Cancer1
2CompletedTreatmentUntreated Operable Early Breast Cancer1
2Not Yet RecruitingTreatmentAnatomic Stage IV Breast Cancer AJCC v8 / Estrogen Receptor Positive / HER2/Neu Negative / Metastatic Breast Carcinoma / Metastatic Malignant Neoplasm in the Bone / Progesterone Receptor Positive / Prognostic Stage IV Breast Cancer AJCC v81
2Not Yet RecruitingTreatmentBreast Cancer Stage II / Breast Cancer Stage III1
2Not Yet RecruitingTreatmentBreast Cancer Stage / Cancer, Breast / HER2 Positive Breast Carcinoma / Her2-Positive Breast Cancer / Metastatic Breast Cancer (MBC) / Recurrent Breast Cancer1
2Not Yet RecruitingTreatmentCancer, Breast1
2Not Yet RecruitingTreatmentCancer, Breast / Estrogen Receptor Positive Tumor / Her2-Positive Breast Cancer1
2Not Yet RecruitingTreatmentCancer, Breast / HR+/HER2-negative Breast Cancer / Metastasis1
2Not Yet RecruitingTreatmentMalignant Neoplasms of Female Genital Organs1
2Not Yet RecruitingTreatmentMelanoma1
2Not Yet RecruitingTreatmentMetastatic Breast Cancer (MBC)1
2Not Yet RecruitingTreatmentThymic Cancer1
2RecruitingScreeningAdvanced Malignant Solid Neoplasm / Ann Arbor Stage III Childhood Non-Hodgkin Lymphoma / Ann Arbor Stage IV Childhood Non-Hodgkin Lymphoma / Childhood Langerhans Cell Histiocytosis / Histiocytic Sarcoma (HS) / Juvenile Xanthogranuloma / Langerhans Cell Histiocytosis (LCH) / Malignant Gliomas / Malignant Lymphomas / Recurrent Central Nervous System Neoplasm / Recurrent Childhood Ependymoma / Recurrent Childhood Malignant Germ Cell Tumor / Recurrent Childhood Medulloblastoma / Recurrent Childhood Non-Hodgkin Lymphoma / Recurrent Childhood Rhabdomyosarcoma / Recurrent Childhood Soft Tissue Sarcoma / Recurrent Ewing Sarcoma / Recurrent Gliomas / Recurrent Hepatoblastoma / Recurrent Langerhans Cell Histiocytosis / Recurrent Malignant Solid Neoplasm / Recurrent Neuroblastoma / Recurrent Osteosarcoma / Recurrent Peripheral Primitive Neuroectodermal Tumor / Recurrent Rhabdoid Tumor / Refractory Central Nervous System Neoplasm / Refractory Childhood Malignant Germ Cell Tumor / Refractory Ewing Sarcoma / Refractory Glioma / Refractory Hepatoblastoma / Refractory Langerhans cell histiocytosis / Refractory Malignant Solid Neoplasm / Refractory Medulloblastoma / Refractory Neuroblastoma / Refractory Non-Hodgkin's lymphoma / Refractory Osteosarcoma / Refractory Peripheral Primitive Neuroectodermal Tumor / Refractory Rhabdoid Tumor / Refractory Rhabdomyosarcoma / Rhabdoid Tumors / Stage III Childhood Non-Hodgkin Lymphoma / Stage III Osteosarcoma / Stage III Osteosarcoma AJCC v7 / Stage III Soft Tissue Sarcoma / Stage III Soft Tissue Sarcoma AJCC v7 / Stage IV Childhood Non-Hodgkin Lymphoma / Stage IV Osteosarcoma / Stage IV Osteosarcoma AJCC v7 / Stage IV Soft Tissue Sarcoma / Stage IV Soft Tissue Sarcoma AJCC v7 / Stage IVA Osteosarcoma / Stage IVA Osteosarcoma AJCC v7 / Stage IVB Osteosarcoma / Stage IVB Osteosarcoma AJCC v7 / Wilms' tumor1
2RecruitingTreatmentAdenocarcinoma of the Colon / Adenocarcinoma of the Rectum / Adult Central Nervous System Germ Cell Tumor / Adult Solid Tumor / Adult Teratoma / Benign Teratoma / Estrogen Receptor-negative Breast Cancer / Estrogen Receptor-Positive Breast Cancer / Familial Testicular Germ Cell Tumor / HER2-Negative Breast Cancer / Her2-Positive Breast Cancer / Male Breast Cancer / Metastatic Colon Cancer / Ovarian Immature Teratoma / Ovarian Mature Teratoma / Ovarian Monodermal and Highly Specialized Teratoma / Progesterone Receptor-negative Breast Cancer / Progesterone Receptor-positive Breast Cancer / Recurrent Breast Cancer / Recurrent Colon Cancer / Recurrent Extragonadal Germ Cell Tumor / Recurrent Extragonadal Non-seminomatous Germ Cell Tumor / Recurrent Extragonadal Seminoma / Recurrent Malignant Testicular Germ Cell Tumor / Recurrent Melanoma / Recurrent Ovarian Germ Cell Tumor / Recurrent Rectal Cancer / Stage III Extragonadal Non-seminomatous Germ Cell Tumor / Stage III Extragonadal Seminoma / Stage III Malignant Testicular Germ Cell Tumor / Stage III Ovarian Germ Cell Tumor / Stage IV Breast Cancer / Stage IV Extragonadal Non-Seminomatous Germ Cell Tumor / Stage IV Extragonadal Seminoma / Stage IV Melanoma / Stage IV Ovarian Germ Cell Tumor / Stage IV Rectal Cancer / Testicular Immature Teratoma / Testicular Mature Teratoma1
2RecruitingTreatmentAdenocarcinomas / Lung Cancer Non-Small Cell Cancer (NSCLC) / Squamous Cell Carcinoma (SCC)1
2RecruitingTreatmentAdvanced Malignant Neoplasm / Advanced Malignant Solid Neoplasm / Bladder Carcinoma / Carcinoma, Breast / Carcinoma, Colorectal / Carcinoma, Pancreatic / Cervical Carcinoma / Colon Carcinoma / Endometrial Carcinoma / Gastric Carcinoma / Gliomas / Head and Neck Carcinoma / Liver and Intrahepatic Bile Duct Carcinoma / Lung, Carcinoma / Malignant Lymphomas / Malignant Uterine Neoplasm / Melanoma / Oesophageal Carcinoma / Ovarian Carcinoma / Plasma Cell Myeloma / Prostate Cancer / Rectal Carcinoma / Recurrent Bladder Carcinoma / Recurrent Breast Carcinoma / Recurrent Cervical Carcinoma / Recurrent Colon Carcinoma / Recurrent Colorectal Carcinoma / Recurrent Esophageal Carcinoma / Recurrent Gastric Carcinoma / Recurrent Gliomas / Recurrent Head and Neck Carcinoma / Recurrent Liver Carcinoma / Recurrent Lung Carcinoma / Recurrent Lymphoma / Recurrent Malignant Solid Neoplasm / Recurrent Melanoma / Recurrent Ovarian Carcinoma / Recurrent Pancreatic Carcinoma / Recurrent Plasma Cell Myeloma / Recurrent Prostate Carcinoma / Recurrent Rectal Carcinoma / Recurrent Skin Carcinoma / Recurrent Solid Neoplasm / Recurrent Thyroid Gland Carcinoma / Recurrent Uterine Corpus Carcinoma / Refractory Lymphomas / Refractory Malignant Neoplasm / Refractory Malignant Solid Neoplasm / Refractory Plasma Cell Myeloma / Renal Carcinoma / Skin Carcinoma / Solid Neoplasms / Thyroid Gland Carcinoma / Uterine Corpus Cancer1
2RecruitingTreatmentAdvanced Malignant Solid Neoplasm / RB1 Positive / Recurrent Childhood Ependymoma / Recurrent Ewing Sarcoma / Recurrent Gliomas / Recurrent Hepatoblastoma / Recurrent Kidney Wilms Tumor / Recurrent Langerhans Cell Histiocytosis / Recurrent Malignant Germ Cell Tumor / Recurrent Malignant Gliomas / Recurrent Medulloblastoma / Recurrent Neuroblastoma / Recurrent Non-Hodgkin Lymphoma / Recurrent Osteosarcoma / Recurrent Peripheral Primitive Neuroectodermal Tumor / Recurrent Rhabdoid Tumor / Recurrent Rhabdomyosarcoma / Recurrent Soft Tissue Sarcoma / Refractory Ependymoma / Refractory Ewing Sarcoma / Refractory Glioma / Refractory Hepatoblastoma / Refractory Langerhans cell histiocytosis / Refractory Malignant Germ Cell Tumor / Refractory Malignant Glioma / Refractory Medulloblastoma / Refractory Neuroblastoma / Refractory Non-Hodgkin's lymphoma / Refractory Osteosarcoma / Refractory Peripheral Primitive Neuroectodermal Tumor / Refractory Rhabdoid Tumor / Refractory Rhabdomyosarcoma / Refractory Soft Tissue Sarcoma1
2RecruitingTreatmentAdvanced Solid Tumors / Multiple Myeloma (MM) / Non-Hodgkin's Lymphoma (NHL)2
2RecruitingTreatmentBreast Cancer Metastatic1
2RecruitingTreatmentBreast Carcinoma Metastatic in the Brain / Estrogen Receptor Negative / HER2/Neu Negative / HER2/Neu Positive / Progesterone Receptor Negative / Recurrent Breast Carcinoma / Stage IV Breast Cancer / Triple-Negative Breast Carcinoma1
2RecruitingTreatmentCancer of the Breast / Cancer, Breast / Carcinoma, Breast1
2RecruitingTreatmentCancer of the Breast / Cancer, Breast / Carcinoma, Breast / Malignant Tumor of Breast1
2RecruitingTreatmentCancer of the Colon / Colon Neoplasms / Malignant Neoplasm of Colon / Neoplasms, Colonic1
2RecruitingTreatmentCancer, Advanced / Sarcomas1
2RecruitingTreatmentCancer, Breast3
2RecruitingTreatmentCancer, Breast / Hormone Receptor Positive Tumor / Human Epidermal Growth Factor 2 Negative Carcinoma of Breast1
2RecruitingTreatmentCarcinoma, Squamous Cell of Head and Neck1
2RecruitingTreatmentChordomas1
2RecruitingTreatmentDCIS1
2RecruitingTreatmentEarly-Stage Breast Carcinoma / Estrogen Receptor Positive Tumor1
2RecruitingTreatmentEarly-Stage Breast Carcinoma / Hormone Receptor Positive Tumor1
2RecruitingTreatmentEndometrial Cancers1
2RecruitingTreatmentEstrogen Receptor Positive Breast Cancer / Hormone Receptor Positive Malignant Neoplasm of Breast / Human Epidermal Growth Factor 2 Negative Carcinoma of Breast / Metastatic Breast Cancer (MBC) / Progesterone Receptor Positive Tumor1
2RecruitingTreatmentEstrogen Receptor Positive / HER2/Neu Negative / One to five years postmenopausal / Recurrent Breast Carcinoma / Stage IV Breast Cancer1
2RecruitingTreatmentEstrogen Receptor and/or Progesterone Receptor Positive / HER2/Neu Negative / Stage IA Breast Cancer / Stage IB Breast Cancer / Stage IIA Breast Cancer / Stage IIB Breast Cancer / Stage IIIA Breast Cancer / Stage IIIB Breast Cancer / Stage IIIC Breast Cancer1
2RecruitingTreatmentEstrogen Receptor-Positive Breast Cancer / HER2/Neu Negative / Stage IV Breast Cancer AJCC v6 and v71
2RecruitingTreatmentFemale Breast Carcinoma1
2RecruitingTreatmentHead and Neck Squamous Cell Carcinoma (HNSCC)1
2RecruitingTreatmentHormone Receptor Positive / Metastatic Breast Cancer (MBC)1
2RecruitingTreatmentLymphoma, B Cell / Mantle Cell Lymphoma (MCL)1
2RecruitingTreatmentMalignant Neoplasm of Female Breast1
2RecruitingTreatmentMetastatic Breast Cancer (MBC)6
2RecruitingTreatmentMetastatic Malignant Neoplasm to Brain1
2RecruitingTreatmentNeoplasms, Breast2
2RecruitingTreatmentOligoastrocytoma / Oligodendrogliomas1
2RecruitingTreatmentProstate Cancer1
2RecruitingTreatmentRare Tumor / Refractory Tumors1
2RecruitingTreatmentSquamous Cell Carcinoma of the Head and Neck (SCCHN)1
2TerminatedTreatmentAnaplastic Astrocytoma (AA) / Glioblastomas / Gliosarcoma1
2TerminatedTreatmentMetastatic Urothelial Carcinoma (UC)1
2WithdrawnTreatmentCancer, Advanced1
2WithdrawnTreatmentEstrogen Receptor Positive / HER2/Neu Negative / Progesterone Receptor Positive / Stage IV Breast Cancer AJCC v6 and v71
2, 3Active Not RecruitingTreatmentCCND1 Gene Amplification / CCND2 Gene Amplification / CCND3 Gene Amplification / CDK4 Gene Amplification / Recurrent Squamous Cell Lung Carcinoma / Stage IV Squamous Cell Lung Carcinoma / Stage IV Squamous Cell Lung Carcinoma AJCC v71
2, 3RecruitingTreatmentRecurrent Squamous Cell Lung Carcinoma / Stage IV Squamous Cell Lung Carcinoma / Stage IV Squamous Cell Lung Carcinoma AJCC v71
3Active Not RecruitingTreatmentCancer, Breast / CPS-EG Score / Her2-normal / Hormonreceptor Positive / Postneoadjuvant Treatment With CDK 4/6 Inhibitor1
3Active Not RecruitingTreatmentMetastatic Breast Cancer (MBC)2
3Active Not RecruitingTreatmentNeoplasms, Breast2
3RecruitingTreatmentAdvanced Breast Cancer (Female) / Advanced Breast Cancer Female1
3RecruitingTreatmentBreast Neoplasm Female1
3RecruitingTreatmentCancer, Breast1
3RecruitingTreatmentEstrogen Receptor Positive Breast Cancer / HER-2 Positive Breast Cancer1
3RecruitingTreatmentMetastatic Breast Cancer (MBC)1
3RecruitingTreatmentNeoplasms, Breast1
4RecruitingTreatmentCancer, Breast1
4RecruitingTreatmentNeoplasms, Breast1
Not AvailableCompletedNot AvailableAdvanced Breast Cancer / Estrogen Receptor-Positive Breast Cancer / Human Epidermal Growth Factor 2 Negative Carcinoma of Breast / Metastatic Breast Cancer (MBC)1
Not AvailableNo Longer AvailableNot AvailableAdvanced Breast Cancer (Female)1
Not AvailableNot Yet RecruitingTreatmentBreast Diseases / Cancer, Breast / Neoplasms, Breast1
Not AvailableRecruitingNot AvailableMalignant Neoplasm of Breast1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
CapsuleOral100 mg/1
CapsuleOral100 mg
CapsuleOral125 mg/1
CapsuleOral125 mg
CapsuleOral75 mg
CapsuleOral75 mg/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US7456168No2008-11-252023-01-16Us
US6936612No2005-08-302023-01-22Us
US7208489No2007-04-242023-01-16Us

Properties

State
Solid
Experimental Properties
PropertyValueSource
pKa7.4 (the secondary piperazine nitrogen) and 3.9 (the pyridine nitrogen)FDA Label
Predicted Properties
PropertyValueSource
Water Solubility0.0174 mg/mLALOGPS
logP2.12ALOGPS
logP2.77ChemAxon
logS-4.4ALOGPS
pKa (Strongest Acidic)11.34ChemAxon
pKa (Strongest Basic)8.86ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count8ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area103.35 Å2ChemAxon
Rotatable Bond Count5ChemAxon
Refractivity127.47 m3·mol-1ChemAxon
Polarizability49.69 Å3ChemAxon
Number of Rings5ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as pyridinylpiperazines. These are compounds containing a pyridinylpiperazine skeleton, which consists of a pyridine linked (not fused) to a piperazine by a bond by a single bond that is not part of a ring.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Diazinanes
Sub Class
Piperazines
Direct Parent
Pyridinylpiperazines
Alternative Parents
N-arylpiperazines / Pyrido[2,3-d]pyrimidines / Aryl alkyl ketones / Dialkylarylamines / Pyridinones / Aminopyridines and derivatives / Aminopyrimidines and derivatives / Methylpyridines / Imidolactams / Vinylogous amides
show 7 more
Substituents
N-arylpiperazine / Pyridinylpiperazine / Pyridopyrimidine / Pyrido[2,3-d]pyrimidine / Tertiary aliphatic/aromatic amine / Aryl ketone / Aryl alkyl ketone / Dialkylarylamine / Aminopyrimidine / Aminopyridine
show 22 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
piperidines, tertiary amino compound, secondary amino compound, ring assembly, aromatic ketone, cyclopentanes, pyridopyrimidine, aminopyridine (CHEBI:85993)

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Cyclin-dependent protein serine/threonine kinase regulator activity
Specific Function
Ser/Thr-kinase component of cyclin D-CDK4 (DC) complexes that phosphorylate and inhibit members of the retinoblastoma (RB) protein family including RB1 and regulate the cell-cycle during G(1)/S tra...
Gene Name
CDK4
Uniprot ID
P11802
Uniprot Name
Cyclin-dependent kinase 4
Molecular Weight
33729.55 Da
References
  1. Fry DW, Harvey PJ, Keller PR, Elliott WL, Meade M, Trachet E, Albassam M, Zheng X, Leopold WR, Pryer NK, Toogood PL: Specific inhibition of cyclin-dependent kinase 4/6 by PD 0332991 and associated antitumor activity in human tumor xenografts. Mol Cancer Ther. 2004 Nov;3(11):1427-38. [PubMed:15542782]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Cyclin-dependent protein serine/threonine kinase activity
Specific Function
Serine/threonine-protein kinase involved in the control of the cell cycle and differentiation; promotes G1/S transition. Phosphorylates pRB/RB1 and NPM1. Interacts with D-type G1 cyclins during int...
Gene Name
CDK6
Uniprot ID
Q00534
Uniprot Name
Cyclin-dependent kinase 6
Molecular Weight
36938.025 Da
References
  1. Fry DW, Harvey PJ, Keller PR, Elliott WL, Meade M, Trachet E, Albassam M, Zheng X, Leopold WR, Pryer NK, Toogood PL: Specific inhibition of cyclin-dependent kinase 4/6 by PD 0332991 and associated antitumor activity in human tumor xenografts. Mol Cancer Ther. 2004 Nov;3(11):1427-38. [PubMed:15542782]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
Inhibitor
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
2. Sulfotransferase 2A1
Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate

Drug created on May 14, 2015 14:03 / Updated on December 18, 2018 05:46