Identification of GZD824 as an Orally Bioavailable Inhibitor That Targets Phosphorylated and Nonphosphorylated Breakpoint Cluster Region–Abelson (Bcr-Abl) Kinase and Overcomes Clinically Acquired Mutation-Induced Resistance against Imatinib

Abstract

Bcr-Abl(T315I) mutation-induced imatinib resistance remains a major challenge for clinical management of chronic myelogenous leukemia (CML). Herein, we report GZD824 (10a) as a novel orally bioavailable inhibitor against a broad spectrum of Bcr-Abl mutants including T315I. It tightly bound to Bcr-Abl(WT) and Bcr-Abl(T315I) with K(d) values of 0.32 and 0.71 nM, respectively, and strongly inhibited the kinase functions with nanomolar IC(50) values. The compound potently suppressed proliferation of Bcr-Abl-positive K562 and Ku812 human CML cells with IC(50) values of 0.2 and 0.13 nM, respectively. It also displayed good oral bioavailability (48.7%), a reasonable half-life (10.6 h), and promising in vivo antitumor efficacy. It induced tumor regression in mouse xenograft tumor models driven by Bcr-Abl(WT) or the mutants and significantly improved the survival of mice bearing an allograft leukemia model with Ba/F3 cells harboring Bcr-Abl(T315I). GZD824 represents a promising lead candidate for development of Bcr-Abl inhibitors to overcome acquired imatinib resistance.

The lung is a host defense niche for immediate neutrophil-mediated vascular protection

“…Mice received intravenous GZD824 (5 μg/gram, i.v. ), currently the most potent and specific pharmacological inhibitor of abl (61, 62), thirty minutes prior to LPS administration. Remarkably, neutrophils were incapable of enhanced crawling even after 30 min.…”

PI3K isoform inhibition associated with anti Bcr-Abl drugs shows in vitro increased anti-leukemic activity in Philadelphia chromosome-positive B-acute lymphoblastic leukemia cell lines

“…The second generation tyrosine kinase inhibitor (TKI) Nilotinib shows both a stronger potency than Imatinib and also acts against most Imatinib-unresponsive Bcr-Abl mutation variants [6–8]. A new, third generation orally bioavailable Bcr-Abl inhibitor, GZD824, has been recently developed, with potency against a wide range of Bcr-Abl mutants [9]. In general, Ph + B-ALL is less sensitive to TKIs that CML.…”

Expanding the structural diversity of Bcr-Abl inhibitors: Dibenzoylpiperazin incorporated with 1H-indazol-3-amine

“…15 This alteration prevents inhibitors form binding efficiently to Bcr-Abl T315I . Fortunately, molecular docking confirmed the binding mode of compound (11a) was more favorable than imatinib (Fig.…”

“…Structural optimization of Bcr-Abl inhibitors remains a focus, and Bcr-Abl T315I mutation remains a major challenge for treatment of CML [15]. Much effort has been devoted to the discovery of ATPcompetitive inhibitors with potency for Bcr-Abl WT and Bcr-Abl T315I [16].…”