Discovery of Highly Isoform Selective Thiazolopiperidine Inhibitors of Phosphoinositide 3-Kinase γ

Abstract

A series of high affinity second-generation thiazolopiperidine inhibitors of PI3Kγ were designed based on some general observations around lipid kinase structure. Optimization of the alkylimidazole group led to inhibitors with higher levels of PI3Kγ selectivity. Additional insights into PI3K isoform selectivity related to sequence differences in a known distal hydrophobic pocket are also described.

Discovery of a Selective Phosphoinositide-3-Kinase (PI3K)-γ Inhibitor (IPI-549) as an Immuno-Oncology Clinical Candidate

“…However, 8-alkyne substitutions (16 and 17) unexpectedly provided modest improvements in potency for PI3K-γ over the 8-chloro substitution in 1. Importantly, the methyl alkyne analogue 17 also demonstrated weaker activity against PI3K-δ compared to 1 and 16, and thus, 17 had >40-fold selectivity for PI3K-γ over PI3K-δ, suggesting that the alkyne substitution makes significant nonfavorable interactions with PI3K-δ at the nonconserved residues adjacent to the specificity pocket (Lys802 for PI3K-γ versus Thr750 for PI3K-δ) as does the aminopyrazolopyrimidine at the hinge binding region 21,22 (see Supporting Information, Figure S1). Various substituted alkyne analogues at the 8-position that extended further into the nonconserved pocket were then prepared and evaluated for PI3K-γ potency and selectivity (Table 3).…”

Insight into the selective mechanism of phosphoinositide 3‐kinase γ with benzothiazole and thiazolopiperidine γ‐specific inhibitors by in silico approaches

“…() and Collier, Messersmith, et al. (). Ligands 2a – 24a were a series of benzothiazole isoform‐selective inhibitors of PI3Kγ, and the core of molecular 3b – 19b was replaced by thiazolopiperidine scaffold.…”

“…As shown in Supporting Information Table S1, the 2D structures and their affinities of PI3Kγ were collected from the previous researches by Collier, Martinez-Botella, et al (2015) and Collier, Messersmith, et al (2015). Ligands 2a-24a were a series of benzothiazole isoform-selective inhibitors of PI3Kγ, and the core of molecular 3b-19b was replaced by thiazolopiperidine scaffold.…”

“…() and Collier, Messersmith, et al. () drew our attention. Herein, we uncovered the binding patterns and investigated the key interactions between the inhibitors and PI3Kγ by molecular modeling techniques.…”

“…The successful development of these inhibitors indicates that it is possible to produce exquisitely specific PI3Kγ inhibitors and some researches provide useful information to reveal the PI3Kγselective mechanism. At this time, a series of benzothiazole and thiazolopiperidine isoform-selective inhibitors of PI3Kγ with the remarkable inhibitory activity and isoform selectivity reported by Collier, Martinez-Botella, et al (2015) and Collier, Messersmith, et al (2015) drew our attention. Herein, we uncovered the binding patterns and investigated the key interactions between the inhibitors and PI3Kγ by molecular modeling techniques.…”