PF-4989216

本公司产品仅用于科研实验，不得用于人体或动物的临床与诊断

PF-4989216 是一种有效的选择性 PI3K 抑制剂，对 p110α、p110β、p110γ、p110δ 和 VPS34 的 IC50 分别为 2 nM、142 nM、65 nM、1 nM 和 110 nM。

PF-4989216 is a novel potent and selective PI3K inhibitor. PF-4989216 inhibits the phosphorylation of PI3K downstream molecules and subsequently leads to inhibition in cell proliferation and xenograft tumor growth in NSCLCs harboring a PIK3CA mutation, including an erlotinib resistant line, NCI-H1975. PF-4989216 inhibited PI3K downstream signaling and subsequently led to apoptosis induction, and inhibition in cell viability, transformation, and xenograft tumor growth in SCLCs harboring PIK3CA mutation.

PF-4989216 (Compound 10) has excellent PI3Kα Ki (0.6 nM), good cellular potency (S473 IC50=79 nM), and good selectivity against mTOR (mTOR Ki=1440 nM). PF-4989216 has PI3Kα Ki less than 1 nM and mTOR Ki more than 1 μM. PF-4989216 also has excellent selectivity over 40 other kinases, and no major CYP inhibitions are observed. Less than 30% inhibition is observed in 1A2, 2C9, 2D6, and 3A4 CYP enzymes at 3 μM. The toxicity of PF-4989216 in several drug-sensitive and MDR cancer cell lines, including cells overexpressing ABCB1 or ABCG2, and in HEK293 cells transfected with human ABCB1 or ABCG2 is determined. PF-4989216 inhibits human colon carcinoma S1 cell line and ABCG2-overexpressing subline S1-M1-80 with IC50s of 1.11±0.09 and 6.79±1.00 uM, respectively. PF-4989216 inhibits human breast carcinoma MCF-7 and ABCG2-overexpressing sublines MCF7-FLV1000 and MCF7-AdVp3000 IC50s of 2.30±0.68, 23.26±2.94 and 62.57±5.46 uM, respectively. PF-4989216 inhibitspcDNA-HEK293, ABCB1-transected MDR19-HEK293, ABCG2-tranfected R482-HEK293cells with IC50s of 0.44±0.05, 0.38±0.06 and 5.05±0.89 uM, respectively.

PF-4989216 (Compound 10) is dosed orally in our in vivo antitumor model, PI3K driven NCI-H1975 xenograft tumors. PF-4989216 demonstrates dose responsive tumor growth inhibitory activity from 25 to 200 mg/kg in QD oral dosing.

PF4989216 | PF 4989216 | PF-4989216

Tyrosine Kinase

BTK

p110δ|p110α|p110γ|Vps34|p110β

Cancer

——

1276553-09-3

380.4

C18H13FN6OS

>98% (HPLC)

DMSO : ≥ 29 mg/mL. 76.24 mM

FC1=C(C=CC(=C1)C#N)C1=C(SC(N2CCOCC2)=C1C#N)C1=NC=NN1

4-(4-cyano-2-fluorophenyl)-2-morpholino-5-(1H-1,2,4-triazol-5-yl)thiophene-3-carbonitrile

(-20℃)

With Ice Pack

≥ 2 years