Discovery of Clinical Development Candidate GDC-0084, a Brain Penetrant Inhibitor of PI3K and mTOR.
Discovery of Clinical Development Candidate GDC-0084, a Brain Penetrant Inhibitor of PI3K and mTOR.
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DOI：
10.1021/acsmedchemlett.6b00005
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发表时间：
2016-04-14
影响因子：
4.2
通讯作者：
Olivero AG
中科院分区：
文献类型：
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作者：
Heffron TP;Ndubaku CO;Salphati L;Alicke B;Cheong J;Drobnick J;Edgar K;Gould SE;Lee LB;Lesnick JD;Lewis C;Nonomiya J;Pang J;Plise EG;Sideris S;Wallin J;Wang L;Zhang X;Olivero AG
抑制磷脂酰肌醇3-激酶(PI3K)信号转导是治疗脑肿瘤特别是多形性胶质母细胞瘤(GBM)的有效方法。我们之前披露了我们的成功方法，即前瞻性地设计有效的、穿透血脑屏障(BBB)的PI3K抑制剂。之前披露的分子最终被认为不适合临床开发，因为预计人类的代谢稳定性较差。因此，我们扩大了我们的研究范围，以确定一种PI3K的血脑屏障穿透抑制剂，该抑制剂预计在人类体内也是代谢稳定的。与我们之前的努力相比，这些努力需要鉴定一种不同的PI3K抑制剂支架，并最终鉴定出GDC-0084(16)。该分子的发现和临床前特征描述在。
Inhibition of phosphoinositide 3-kinase (PI3K) signaling is an appealing approach to treat brain tumors, especially glioblastoma multiforme (GBM). We previously disclosed our successful approach to prospectively design potent and blood–brain barrier (BBB) penetrating PI3K inhibitors. The previously disclosed molecules were ultimately deemed not suitable for clinical development due to projected poor metabolic stability in humans. We, therefore, extended our studies to identify a BBB penetrating inhibitor of PI3K that was also projected to be metabolically stable in human. These efforts required identification of a distinct scaffold for PI3K inhibitors relative to our previous efforts and ultimately resulted in the identification of GDC-0084 (16). The discovery and preclinical characterization of this molecule are described within.