Virtual Screening Identifies Irreversible FMS-like Tyrosine Kinase 3 Inhibitors with Activity toward Resistance-Conferring Mutations

Abstract

The use of covalent irreversible binding inhibitors is an established concept for drug development. Usually the discovery of new irreversible kinase inhibitors occurs serendipitously showing that efficient rational approaches for the rapid discovery of new drugs are needed.Herein, we report a virtual screening strategy that led to the discovery of irreversible inhibitors of the FMS-like tyrosine kinase 3 (FLT3) involved in the pathogenesis of acute myeloid leukemia (AML). A virtual screening library was designed to target the highly conserved Cys828 residue preceding the DFG motif by modification of reported reversible inhibitors with chemically reactive groups. Prospective covalent docking allowed the identification of two lead series, resulting in a massive increase in inhibition of kinase activity and cell viability by irreversible inhibitors compared to the corresponding reversible scaffolds. Lead compound 4b (BSc5371) displays superior cytotoxicity in FLT3-dependent cell lines to compounds in recent clinical trials and overcomes drug-resistant mutations.

An automatic pipeline for the design of irreversible derivatives identifies a potent SARS-CoV-2 Mpro inhibitor

“…Historically, most covalent inhibitors were designed by the addition of an electrophile to an already known reversible inhibitor that suitably binds next to a cysteine residue (Angst et al, 2020;Dubiella et al, 2015;Hagel et al, 2015;Vazquez-Rodriguez and Wright, 2019;Ward et al, 2015;Weisner et al, 2015). More recently, covalent inhibitors are also being discovered by empirical screening of covalent fragment libraries (Backus et al, 2016;Craven et al, 2018;Johansson et al, 2019;Kathman et al, 2014Kathman et al, , 2015Parker et al, 2017;Resnick et al, 2019) and by covalent virtual screening (Bensinger et al, 2019;Chowdhury et al, 2019;London et al, 2014;Nnadi et al, 2018;Rachman et al, 2019;Scarpino et al, 2018;Shraga et al, 2019;Toledo Warshaviak et al, 2014). While covalent fragment and virtual screening can potentially discover new scaffolds, the binding affinity of primary hits may be relatively low, and often require laborious medicinal chemistry to reach suitable potency.…”

Synthesis, characterization, and biological evaluation of new spebrutinib analogues: potential candidates with enhanced activity and reduced toxicity profiles

“…The overall chemical syntheses are revealed in scheme (1). The following chemical methods were used for the spebrutinib analogue preparations [15] Benzoyl chloride (309 mg, 2.2 mmol) was added to a stirred solution of compound (1) (665 mg, 1.8 mmol) and potassium carbonate (1.24 g, 9 mmol) in THF (12 mL) at 0°C, and the reaction mixture was stirred at 0°C for 45 min.…”

Selective C3-alkenylation of oxindole with aldehydes using heterogeneous CeO2 catalyst

“…Oxindole is used as a neurodepressant tryptophan metabolite and physiologically present in mammalian brain/blood, and can influence brain functions [2]. 3-Alkyledene-oxindole derivatives are medicinally important and exist in anticancer kinase inhibitors and anti-inflammatory drugs including Sunitinid and Tedinap, respectively [3][4][5]. They are also well-known synthetic intermediates of natural products named TMC-95, Gelsemine and biologically appealing spirooxindoles [6][7][8][9][10][11][12][13].…”