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A novel thiazolopyrimidinone series of PI3K-beta selective inhibitors has been identified. This chemotype has provided an excellent tool compound, 18, that showed potent growth inhibition in the PTEN-deficient breast cancer cell line MDA-MB-468 under anchorageindependent conditions, and it also demonstrated pharmacodynamic effects and efficacy in a PTENdeficient prostate cancer PC-3 xenograft mouse model. KEYWORDS: PI3K-beta inhibitor, PTEN-deficient, phosphatidylinositol 3-kinase, homology model, structure−activity relationship S ince 2006, numerous small molecule phosphatidylinositol 3-kinase (PI3K) inhibitors have entered a wide range of clinical trials, primarily as targeted anticancer agents. 1,2 These molecules are either class I pan-PI3K inhibitors (with or without mTOR activity) or PI3K-alpha selective or PI3K-delta selective inhibitors. Despite many years of effort, it remains unclear what PI3K target selectivity profile is required of an inhibitor to provide a safe and effective agent for a specific patient population. Recent preclinical studies have shown that, in a PTEN-loss context, tissue-specific deletion of the PI3K-beta isoform in the prostate specifically reduces PI3K signaling and blocks the formation of aggressive prostate tumors. 3 Driven by these intriguing data, a couple of academic groups have published their efforts on identifying novel beta-isoform selective small molecule tools or using an existing tool molecule to understand the biology and the pathway in depth. 4 In previous communications, 5 we have reported on the discovery of two novel series of PI3K-beta inhibitors, imidazo[1,2-a]-pyrimidin-5(1H)-ones and 1,2,4-triazolo[1,5-a]pyrimidin-7(3H)-ones, which are exemplified by compounds 1 and 2 (Figure 1). Although these are excellent tool molecules for understanding PI3K-beta biology at a cellular level, they are limited from in vivo target validation due to the poor rodent pharmacokinetic profile. 6 The modeling and SAR results from our two previous series have suggested that a potent and selective PI3K-beta inhibitor could be designed from a bicyclic core structure bearing substituents designed to make three key binding interactions: (a) a carbonyl group to interact with the back-pocket Tyr-839; (b) a morpholine to act as a hinge binder; and (c) a lipophilic group that can induce a selectivity-pocket formed by Met-779 and Trp-787 (Figure 2A). We soon discovered that thiazolopyrimidinones with a substituted benzyl group at the N1-position met the above requirements (Figure 1).

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