PKI-402

中文名称:

PKI-402

中文同义词:

1-[4-[3-乙基-7-(吗啉-4-基)-3H-[1,2,3]三唑并[4,5-D]嘧啶-5-基]苯基]-3-[4-[(4-甲基哌嗪-1-基)羰基]苯基]脲;PI3K/MTOR双重抑制剂(PKI-402)

英文名称:

PKI-402

英文同义词:

1-(4-(3-ethyl-7-morpholino-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl)phenyl)-3-(4-(1-methylpiperazine-4-carbonyl)phenyl)urea;1-(4-(3-ethyl-7-morpholino-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl)phenyl)-3-(4-(4-methylpiperazine-1-carbonyl)phenyl)urea;PKI-402;PKI402;1-(4-(3-Ethyl-7-morpholino-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl)phenyl)-3-(4-(4-methylpiper;PKI-402;1-[4-[3-Ethyl-7-(morpholin-4-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-yl]phenyl]-3-[4-[(4-methylpiperazin-1-yl)carbonyl]phenyl]urea;CS-167;Urea, N-[4-[3-ethyl-7-(4-morpholinyl)-3H-1,2,3-triazolo[4,5-d]pyrimidin-5-yl]phenyl]-N-[4-[(4-methyl-1-piperazinyl)carbonyl]phenyl]-

CAS号:

1173204-81-3

分子式:

C29H34N10O3

分子量:

570.65

EINECS号:

相关类别:

信号转导通路激酶抑制剂;细胞生物学试剂;PI3K/Akt/mTOR;Akt;mTOR;PI3K

Mol文件:

1173204-81-3.mol

沸点 

670.6±55.0 °C(Predicted)

密度 

1.43

酸度系数(pKa)

13.80±0.70(Predicted)

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 16 nM (IC 50 ) mTOR 3 nM (IC 50 )

PI3Kα 2 nM (IC 50 )

PI3Kα-H1047R 3 nM (IC 50 )