Discovery and Optimization of a Series of Benzothiazole Phosphoinositide 3-Kinase (PI3K)/Mammalian Target of Rapamycin (mTOR) Dual Inhibitors

Abstract

Phosphoinositide 3-kinase α (PI3Kα) is a lipid kinase that plays a key regulatory role in several cellular processes. The mutation or amplification of this kinase in humans has been implicated in the growth of multiple tumor types. Consequently, PI3Kα has become a target of intense research for drug discovery. Our studies began with the identification of benzothiazole compound 1 from a high throughput screen. Extensive SAR studies led to the discovery of sulfonamide 45 as an early lead, based on its in vitro cellular potency. Subsequent modifications of the central pyrimidine ring dramatically improved enzyme and cellular potency and led to the identification of chloropyridine 70. Further arylsulfonamide SAR studies optimized in vitro clearance and led to the identification of 82 as a potent dual inhibitor of PI3K and mTOR. This molecule exhibited potent enzyme and cell activity, low clearance, and high oral bioavailability. In addition, compound 82 demonstrated tumor growth inhibition in U-87 MG, A549, and HCT116 tumor xenograft models.

Recent development of ATP-competitive small molecule phosphatidylinostitol-3-kinase inhibitors as anticancer agents

“…Angelo et al [90] identified benzothiazole compound 265 (PI3Kα Ki = 53 nM, mTOR Ki > 25 μM) as an initial hit from HTS, and the crystal structure suggested that the ribose pocket might accommodate larger groups than pyrimidine. Extensive SAR studies, including the link atom (sulfur, oxygen and nitrogen) and the pyridine replacing pyrimidine (266-268), led to the sulfonamide 269 (PI3Kα Ki = 38 nM, mTOR Ki = 269 nM) for as an early lead, with high in vitro and in vivo clearance.…”

“…In previous studies, Wurz et al [90] disclosed sulfonamide benzothiazole derivatives (e.g. 366, PI3Kα Ki = 1.2 nM, mTOR IC 50 = 2.1 nM) as potent PI3K/mTOR dual inhibitor, while had low solubility.…”

Pd‐Catalyzed Cross‐Coupling with Organometals Containing Zn, Al, Zr, and so on – The Negishi Coupling and Its Recent Advances

“…Many of the recently reported potential drug candidates [224][225][226][227] and natural products were synthesized by using a Negishi cross-coupling as one of the key steps in the total synthesis. Some of the representative structures of biologically active compounds are shown in Table 3.15.…”

Structure-based optimization leads to the discovery of NSC765844, a highly potent, less toxic and orally efficacious dual PI3K/mTOR inhibitor

“…With substantial structural and biochemical information of PI3K inhibitors available, we searched a number of X-ray co-crystal structures of PI3K subunits bound to small molecule inhibitors and explored the binding modes at the ATP-binding site. [20,[28][29][30][31] The active sites of PI3K subunits were mainly comprised of three key regions: the hinge binder, the affinity pocket 3L08). (C) Sequence alignment between PI3Kα, β, γ and δ.…”

“…[28][29][30][34][35][36][37][38][39][40][41] Crystallographic analysis found that this scaffold fits the active site very well and thus possesses a high ligand efficiency (LE). As shown in Figure 2(B), the quinoline nitrogen forms a hydrogen bond interaction with Val882 (Val851 in PI3Kα) in the hinge binder region of the kinase domain of PI3Kγ.…”