palbociclib   

GtoPdb Ligand ID: 7380

Synonyms: Ibrance® | PD-0332991 | PD0332991
palbociclib is an approved drug (FDA (2015), EMA (2016))
Compound class: Synthetic organic
Comment: Palbociclib is a selective inhibitor of the cyclin-dependent kinases CDK4 and CDK6 [6-7,13]. This kinase inhibitor has anti-tumour activity in several tumour models [6-7,9,14-15].
The pharmaceutical formulation contains palbociclib isethionate (PubChem CID 11478676).
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2D Structure
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Physico-chemical Properties
Hydrogen bond acceptors 8
Hydrogen bond donors 2
Rotatable bonds 5
Topological polar surface area 105.04
Molecular weight 447.24
XLogP 3.29
No. Lipinski's rules broken 0
SMILES / InChI / InChIKey
Canonical SMILES CC(=O)c1c(C)c2cnc(nc2n(c1=O)C1CCCC1)Nc1ccc(cn1)N1CCNCC1
Isomeric SMILES CC(=O)c1c(C)c2cnc(nc2n(c1=O)C1CCCC1)Nc1ccc(cn1)N1CCNCC1
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)
InChI Key AHJRHEGDXFFMBM-UHFFFAOYSA-N
References
1. Beaver JA, Amiri-Kordestani L, Charlab R, Chen W, Palmby T, Tilley A, Zirkelbach JF, Yu J, Liu Q, Zhao L et al.. (2015)
FDA Approval: Palbociclib for the Treatment of Postmenopausal Patients with Estrogen Receptor-Positive, HER2-Negative Metastatic Breast Cancer.
Clin. Cancer Res., 21 (21): 4760-6. [PMID:26324739]
2. Beroukhim R, Mermel CH, Porter D, Wei G, Raychaudhuri S, Donovan J, Barretina J, Boehm JS, Dobson J, Urashima M et al.. (2010)
The landscape of somatic copy-number alteration across human cancers.
Nature, 463 (7283): 899-905. [PMID:20164920]
3. Choi YJ, Li X, Hydbring P, Sanda T, Stefano J, Christie AL, Signoretti S, Look AT, Kung AL, von Boehmer H et al.. (2012)
The requirement for cyclin D function in tumor maintenance.
Cancer Cell, 22 (4): 438-51. [PMID:23079655]
4. Dean JL, McClendon AK, Hickey TE, Butler LM, Tilley WD, Witkiewicz AK, Knudsen ES. (2012)
Therapeutic response to CDK4/6 inhibition in breast cancer defined by ex vivo analyses of human tumors.
Cell Cycle, 11 (14): 2756-61. [PMID:22767154]
5. Finn RS, Crown JP, Lang I, Boer K, Bondarenko IM, Kulyk SO, Ettl J, Patel R, Pinter T, Schmidt M et al.. (2015)
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.
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6. Finn RS, Dering J, Conklin D, Kalous O, Cohen DJ, Desai AJ, Ginther C, Atefi M, Chen I, Fowst C et al.. (2009)
PD 0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell lines in vitro.
Breast Cancer Res., 11 (5): R77. [PMID:19874578]
7. Fry DW, Harvey PJ, Keller PR, Elliott WL, Meade M, Trachet E, Albassam M, Zheng X, Leopold WR, Pryer NK et al.. (2004)
Specific inhibition of cyclin-dependent kinase 4/6 by PD 0332991 and associated antitumor activity in human tumor xenografts.
Mol. Cancer Ther., 3 (11): 1427-38. [PMID:15542782]
8. Johnston SR. (2015)
Enhancing Endocrine Therapy for Hormone Receptor-Positive Advanced Breast Cancer: Cotargeting Signaling Pathways.
J. Natl. Cancer Inst., 107 (10). [PMID:26251289]
9. Porter B. (1983)
Primary care pediatrics vs. family practice: a nonissue.
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A synthetic lethal interaction between K-Ras oncogenes and Cdk4 unveils a therapeutic strategy for non-small cell lung carcinoma.
Cancer Cell, 18 (1): 63-73. [PMID:20609353]
11. Sawai CM, Freund J, Oh P, Ndiaye-Lobry D, Bretz JC, Strikoudis A, Genesca L, Trimarchi T, Kelliher MA, Clark M et al.. (2012)
Therapeutic targeting of the cyclin D3:CDK4/6 complex in T cell leukemia.
Cancer Cell, 22 (4): 452-65. [PMID:23079656]
12. Sun P, Lan J, Peng J, Chen Y, Wang B, Dong Q. (2014)
Thiophene miazines derivate, preparation method therefor, and medical application thereof.
Patent number: WO2014183520A1. Assignee: Shanghai Hengrui Pharmaceutical Co. Priority date: 17/05/2013. Publication date: 20/11/2014.
13. Toogood PL, Harvey PJ, Repine JT, Sheehan DJ, VanderWel SN, Zhou H, Keller PR, McNamara DJ, Sherry D, Zhu T et al.. (2005)
Discovery of a potent and selective inhibitor of cyclin-dependent kinase 4/6.
J. Med. Chem., 48 (7): 2388-406. [PMID:15801831]
14. Wang L, Wang J, Blaser BW, Duchemin AM, Kusewitt DF, Liu T, Caligiuri MA, Briesewitz R. (2007)
Pharmacologic inhibition of CDK4/6: mechanistic evidence for selective activity or acquired resistance in acute myeloid leukemia.
Blood, 110 (6): 2075-83. [PMID:17537993]
15. Wiedemeyer WR, Dunn IF, Quayle SN, Zhang J, Chheda MG, Dunn GP, Zhuang L, Rosenbluh J, Chen S, Xiao Y et al.. (2010)
Pattern of retinoblastoma pathway inactivation dictates response to CDK4/6 inhibition in GBM.
Proc. Natl. Acad. Sci. U.S.A., 107 (25): 11501-6. [PMID:20534551]
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Better Together: Targeted Combination Therapies in Breast Cancer.
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17. Zhang XH, Cheng Y, Shin JY, Kim JO, Oh JE, Kang JH. (2013)
A CDK4/6 inhibitor enhances cytotoxicity of paclitaxel in lung adenocarcinoma cells harboring mutant KRAS as well as wild-type KRAS.
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