Discovery, Optimization, and Evaluation of Potent and Highly Selective PI3Kγ–PI3Kδ Dual Inhibitors

Abstract

An electronic density model was developed and used to identify a novel pyrrolotriazinone replacement for a quinazolinone, a commonly used moiety to impart selectivity in inhibitors for PI3Kγ and PI3Kδ. Guided by molecular docking, this new specificity piece was then linked to the hinge-binding region of the inhibitor using a novel cyclic moiety. Further structure–activity relationship optimization around the hinge region led to the discovery of candidate 26, a highly potent and selective PI3Kγ–PI3Kδ dual inhibitor with favorable drug metabolism and pharmacokinetic properties in preclinical species.

Immunological characterization of HM5023507, an orally active PI3Kδ/γ inhibitor

“…The pharmacokinetic parameters for HM5023507 in female Wistar rats are as follows (mean ± SD, n = 3; iv/po doses of 2.5 and 10 mg/kg, respectively; terminal half‐life‐ 5.1 ± 0.6 hr, plasma clearance‐ 3.3 ± 0.1 mL/min/kg, Vss: 1.2 ± 0.1 L/kg, and oral bioavailability (%F) – 104 ± 18.…”

“…The inhibitory effects of HM5023507 on kinase activity of PI3K were determined in enzymatic assays in vitro or in a cellular context as per methods described elsewhere and summarized in the Supplemental Materials and Methods Section.…”

“…Blood samples were collected under anesthesia at the designed time points postdose and stimulated with anti‐IgD at 37°C overnight. After red blood cell (RBC) lysis, leukocytes were harvested, and B cells were stained with anti‐B220 and anti‐CD86 antibodies (both from eBioscience) for flow cytometry analysis . Activated B cells were gated based on B220 and CD86 signal.…”

“…CIA was induced as per methods outlined in Jia et al Briefly, female Wistar rats were anesthetized with isoflurane, and 200 μg of bovine type II collagen (Chondrex, Redmond, WA) in Freund's incomplete adjuvant (Sigma‐Aldrich) was injected intradermally at the base of the tail on days 0 and 6. HM5023507 dissolved in HPCD or vehicle (HPCD) were dosed orally from day 10 onwards.…”

“…Our efforts to identify such inhibitors resulted in the identification of HM5023507 (Figure ) whose preclinical pharmacology is summarized in this report. The structure‐activity relationships and the medicinal chemistry efforts leading up to the identification of HM5023507 are summarized elsewhere …”