Preclinical Development of PQR514, a Highly Potent PI3K Inhibitor Bearing a Difluoromethyl-Pyrimidine Moiety
Preclinical Development of PQR514, a Highly Potent PI3K Inhibitor Bearing a Difluoromethyl-Pyrimidine Moiety
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DOI：
10.1021/acsmedchemlett.9b00333
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发表时间：
2019-10-01
影响因子：
4.2
通讯作者：
Wymann, Matthias P.
中科院分区：
文献类型：
--
作者：
Borsari, Chiara;Rageot, Denise;Wymann, Matthias P.
磷酸肌醇3-激酶（PI 3 K）/雷帕霉素（mTOR）机制靶点通路是细胞生长的关键调节因子，在癌症中经常过度活化。因此，PI 3 K抑制剂代表了癌症治疗中的宝贵资产。在此，我们开发了一种新型抗癌药物，强效泛PI 3 K抑制剂PQR 514（4），它是II期临床化合物PQR 309（1）的后续化合物。化合物4相对于其前体化合物在体外和细胞测定中具有改善的效力。它在抑制癌细胞增殖方面表现出优效性，并在OVCAR-3异种移植模型中显示出显著的抗肿瘤活性，浓度约为PQR 309的八分之一（1）。有利的药代动力学特征和最小的脑渗透促进PQR 514（4）作为治疗全身性肿瘤的最佳候选药物。
The phosphoinositide 3-kinase (PI3K)/mechanistic target of rapamycin (mTOR) pathway is a critical regulator of cell growth and is frequently hyperactivated in cancer. Therefore, PI3K inhibitors represent a valuable asset in cancer therapy. Herein we have developed a novel anticancer agent, the potent pan-PI3K inhibitor PQR514 (4), which is a follow-up compound for the phase-II clinical compound PQR309 (1). Compound 4 has an improved potency both in vitro and in cellular assays with respect to its predecessor compounds. It shows superiority in the suppression of cancer cell proliferation and demonstrates significant antitumor activity in an OVCAR-3 xenograft model at concentrations approximately eight times lower than PQR309 (1). The favorable pharmacokinetic profile and a minimal brain penetration promote PQR514 (4) as an optimized candidate for the treatment of systemic tumors.