Description
PD0332991 Isethionate is a highly selective inhibitor of CDK4/6 with IC50 of 11 nM/16 nM. It shows no activity against CDK1/2/5, EGFR, FGFR, PDGFR, InsR, etc. Phase 2/3.
Storage
2 years -20 centigrade Powder; 2 weeks 4 centigrade in DMSO; 6 months -80 centigrade in DMSO.
Molecular Formula
C24H29N7O2.C2H6O4S
Chemical Name
Ethanesulfonic acid, 2-hydroxy-, compd. with 6-acetyl-8-cyclopentyl-5-methyl-2-[[5-(1-piperazinyl)-2-pyridinyl]amino]pyrido[2,3-d]pyrimidin-7(8H)-one (1:1)
Solubility
DMSO <1 mg/mL; Water 100 mg/mL; Ethanol <1 mg/mL
In vitro
PD 0332991 exhibits absolute selectivity for CDK4/6 with little or no activity against other CDKs. PD 0332991 is effective at reducing Rb phosphorylation at Ser780 and Ser795 in MDA-MB-435 breast carcinoma cells with IC50 of 66 nM and 63 nM, respectively. PD 0332991 is a potent inhibitor of cell growth and suppresses DNA replication by preventing cells from entering S phase. PD 0332991 inhibits thymidine incorporation into the DNA of Rb-positive human breast (such as MDA-MB-435, MCF-7), colon (H1299), and lung carcinomas (Colo-205) as well as human leukemias (CRRF-CEM and K562), with IC50 values ranging from 0.04-0.17 μM. PD 0332991 significant increases the percentage of MDA-MB-453 in G1 period. PD 0332991 inhibits phosphorylation of Rb in cycling CD138+ primary bone marrow myeloma cells, nontransformed primary B cells, MM1.S and CAG HMCLs cells line with IC50 of <0.1 μM, 0.05 μM, and 60-70 nM, respectively. PD 0332991 treatment also induces G1 arrest of CD138+ primary bone marrow myeloma and nontransformed primary B cells. PD 0332991 induces G1 arrest in MM1.S with IC50 of ~0.05 μM.PD 0332991 preferentially inhibits proliferation of luminal estrogen receptor-positive (including HER2-positive) human breast cancer cell lines. PD 0332991 increases gene expression of pRb and cyclin D1 and decreases gene expression of CDKN2A (p16) in most sensitive lines. PD 0332991 enhances sensitivity to tamoxifen in cell lines with conditioned resistance to ER blockade.
In vivo
PD 0332991(150 mg/kg) produces rapid Colo-205 colon carcinoma xenografts regressions and a corresponding tumor growth delay. PD 0332991 (150 mg/kg) induces complete tumor stasis and cell kill in MDA-MB-435 breast carcinoma. PD 0332991 (150 mg/kg) also induces significant tumor regression in mice bearing the SF-295 glioblastoma xenografts, and in ZR-75-1 breast and PC-3 prostate tumor models (complete suppression of tumor growth). PD 0332991 (150 mg/kg) suppresses Rb Ser780 phosphorylation in MDA-MB-435 breast carcinoma over the full 24-hour period. PD 0332991 (150 mg/kg) down-regulates expression of four E2F-regulated genes CDC2, CCNE2, TK1, and TOP2A in Colo-205 carcinoma xenografts. PD 0332991 also rapidly inhibits myeloma tumor growth.
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