PKI-402

生物活性体外研究体内研究靶点 PKI-402 试剂级价格

PKI-402

CAS号:1173204-81-3
英文名:PKI-402
中文名:PKI-402
CBNumber:CB22582890
分子式:C29H34N10O3
分子量:570.65
MOL File:1173204-81-3.mol

PKI-402化学性质

沸点 :670.6±55.0 °C(Predicted)
密度 :1.43
储存条件 :Store at -20°C
溶解度 :insoluble in EtOH; insoluble in H2O; ≥14.28 mg/mL in DMSO
形态 :solid
酸度系数(pKa) :13.80±0.70(Predicted)
颜色 :White to off-white

PKI-402性质、用途与生产工艺

生物活性 PKI-402是一种有效的，pan-PI3K/mTOR双重抑制剂，靶向作用于PI3Kα/β/γ/δ和mTOR，IC50分别为2 nM/7 nM/16 nM/14 nM和3 nM，也有效作用于PI3Kα突变型E545K和H1047R。
体外研究 Equivalent to the IC50 for wild-type PI3Kα, PKI-402 inhibits E545K and H1047R PI3Kα mutants with IC50 of 3 nM. In a panel of 236 human protein kinases, PKI-402 only displays inhibitory activity against C-Raf and B-Raf with IC50 of 7 μM, and displays little activity against all other kinases with IC50 of > 10 μM. PKI-402 inhibits the growth of human tumor cell lines with IC50 of 6-349 nM. Consistently, PKI-402 inhibits phosphorylation of PI3K and mTOR effector proteins, particularly phosphorylated Akt (p-Akt) at T308 and S473 with IC50 of <10 nM and <30 nM, respectively. PKI-402 inhibits both p70S6K and 4EBP1 phosphorylation with IC50 of <10 nM. PKI-402 inhibits Akt phosphorylation of PRAS40 at T246 with IC50 of <30 nM, and inhibits Akt phosphorylation of ENOS at S1177 and GSK3α/GSK3β at S9/S21 with IC50 of <10 nM. In MDAMB-361, a breast tumor line with mutant PI3K-α (E545K) and elevated levels of Her2 receptor, PKI-402 treatment induces cleaved poly(ADP-ribose) polymerase (PARP), a marker for apoptosis. Less than 10% of MDAMB-361 cells exposed to PKI-402 at 0.3 μM (or higher) for 24 hours remain viable.
体内研究 Single dose of PKI-402 (100 mg/kg) suppresses Akt phosphorylation (at T308) and induces cleaved PARP in MDA-MB-361 tumors. In normal tissue (heart and lung), PKI-402 (100 mg/kg) has minimal effect on p-Akt, with no detectable cleaved PARP. Consistently, PKI-402 at 100 mg/kg (daily for 5 days, one round) reduces initial tumor volume of 260 mm3 to 129 mm3 and prevents tumor regrowth for 70 days in MDA-MB-361. PKI-402 significantly inhibits the growth of A549 tumors in nude mice at 25 mg/kg and 50 mg/kg. PKI-402 at 100 mg/kg (daily for 5 days, one round) causes significant (P < 0.01) reduction in tumor growth of U87MG.

靶点

PI3Kα

2 nM (IC ₅₀ )

PI3Kα-H1047R

3 nM (IC ₅₀ )

PI3Kα-E545K

3 nM (IC ₅₀ )

PI3Kβ

7 nM (IC ₅₀ )

PI3Kδ

14 nM (IC ₅₀ )

PI3Kγ