Discovery of 2-{3-[2-(1-Isopropyl-3-methyl-1H-1,2–4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl]-1H-pyrazol-1-yl}-2-methylpropanamide (GDC-0032): A β-Sparing Phosphoinositide 3-Kinase Inhibitor with High Unbound Exposure and Robust in Vivo Antitumor Activity

Abstract

Dysfunctional signaling through the phosphoinositide 3-kinase (PI3K)/AKT/mTOR pathway leads to uncontrolled tumor proliferation. In the course of the discovery of novel benzoxepin PI3K inhibitors, we observed a strong dependency of in vivo antitumor activity on the free-drug exposure. By lowering the intrinsic clearance, we derived a set of imidazobenzoxazepin compounds that showed improved unbound drug exposure and effectively suppressed growth of tumors in a mouse xenograft model at low drug dose levels. One of these compounds, GDC-0032 (11l), was progressed to clinical trials and is currently under phase I evaluation as a potential treatment for human malignancies.

PI3′-Kinase Inhibition Forestalls the Onset of MEK1/2 Inhibitor Resistance in BRAF-Mutated Melanoma

“…To test if BRAF V600E /PTEN Null melanoma cells require PI3Kβ to promote PI3′-lipid signaling with downstream effects on cell proliferation we employed GDC-0032, a PI3Kβ-sparing class I PI3K inhibitor that inhibits PI3Kα, δ and γ (29). Initially, we compared the anti-proliferative activity of GDC-0032 to that of GDC-0941, a pan-class I PI3K inhibitor (30).…”

Taselisib, a selective inhibitor of PIK3CA, is highly effective on PIK3CA-mutated and HER2/neu amplified uterine serous carcinoma in vitro and in vivo

“…Clinically, the benefit of targeting a specific isoform of PIK3 has led to more complete target inhibition at lower doses resulting in less adverse effects [41]. In preclinical studies, taselisib demonstrated antitumor activity, inducing tumor growth arrest and regression in PIK3CA mutated xenograft models [21]. Thanks to promising in vitro and in vivo results, taselisib is currently undergoing Phase I/II clinical trials in patients with advanced solid breast cancer (NCT01296555).…”

“…Unlike other PIK3CA inhibitors previously studied in USC by our group (i.e., GDC-0980) [20], taselisib binds the ATP-binding pocket of PI3K with selective preference for the mutated form of PIK3CA [21]. This selectivity profile has been shown to allow for greater sensitivity in vivo at the maximum tolerated dose relative to a pan inhibitor in representative PIK3CA-mutant xenografts [21] [22].…”

“…Unlike other PIK3CA inhibitors previously studied in USC by our group (i.e., GDC-0980) [20], taselisib binds the ATP-binding pocket of PI3K with selective preference for the mutated form of PIK3CA [21]. This selectivity profile has been shown to allow for greater sensitivity in vivo at the maximum tolerated dose relative to a pan inhibitor in representative PIK3CA-mutant xenografts [21] [22]. On the basis of this evidence the aims of this study were: 1) to evaluate the in vitro sensitivity of a panel of 9 well characterized primary USC cell lines to taselisib; 2) to compare the activity of taselisib in USC harboring amplification of HER2/neu and PIK3CA mutations versus control USC cell lines harboring wild type PIK3CA or lacking amplification of HER2/neu; 3) to evaluate the effect of taselisib on cell-cycle distribution; 4) to assess changes in phosphoprotein S6 (pS6) as downstream cellular response to taselisib exposure in vitro ; 5) to evaluate the in vivo effect of taselisib in a preclinical mouse model harboring a USC xenograft with HER2/neu amplification and PIK3CA mutation.…”

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

“…Then Ndubaku et al [100] (Genentech) derived a set of imidazobenzoxazepin compounds, by modification of compound 307, which displayed good in vitro potency (PI3Kα IC 50 <0.5 µΜ), while had low solubility and high in vivo unbound clearance. These imidazobenzoxazepin derivatives (308, PI3Kα IC 50 ~ 0.1- 21.1 nM) had better tumor growth inhibition in vivo , and GDC-0032 (309, PI3Kα/β/δ/γ IC 50 =0.29/9.1/ 0.12/ 0.97 nM) was identified, which was undergoing clinical development for use in PI3K-related cancers.…”