Discovery of a Novel Mutant-Selective Epidermal Growth Factor Receptor Inhibitor Using in silico Enabled Drug Discovery Platform

Despite the success of first, second and third generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in treatment of non-small cell lung cancer (NSCLC) with classical EGFR mutations (L858R or Exon 19 deletions), disease progression often occurs due to the acquisition of additional mutations in the EGFR kinase domain that confer TKI resistance. Specifically, acquisition of both T790M and C797S resistance mutations results in an EGFR variant that is resistant to all approved EGFR TKIs. Herein, we report a physics-based computationally-driven lead identification approach which successfully identified structurally-unique imidazo[3.2-b]pyrazole derivatives as reversible inhibitors of EGFR classical mutations bearing both T790M and C797S. Importantly, they spare EGFR WT to avoid known EGFR WT-driven cutaneous toxicities. During profiling of imidazo[3.2-b]pyrazole derivatives, we elucidated the bioactivation mechanism causing CYP3A4/5 time-dependent inhibition (TDI) and found key modifications to suppress bioactivation and mitigate the TDI risk. Representative lead compound 31 inhibited EGFR L858R/T790M/C797S in biochemical assays with a Ki = 2.1 nM, and EGFR del19/T790M/C797S in a Ba/F3 cellular assay with a IC50 = 56.9 nM. Deuterated analog of 31 (38) demonstrated dose-dependent tumor growth inhibition in a Ba/F3 EGFR del19/T790M/C797S CDX model by 47% at 50 mg/kg BID and 92% at 100 mg/kg BID

Discovery and Optimization of Indolyl-Containing 4‑Hydroxy-2-Pyridone Type II DNA Topoisomerase Inhibitors Active against Multidrug Resistant Gram-negative Bacteria

There exists an urgent medical need to identify new chemical entities (NCEs) targeting multidrug resistant (MDR) bacterial infections, particularly those caused by Gram-negative pathogens. 4-Hydroxy-2-pyridones represent a novel class of nonfluoroquinolone inhibitors of bacterial type II topoisomerases active against MDR Gram-negative bacteria. Herein, we report on the discovery and structure–activity relationships of a series of fused indolyl-containing 4-hydroxy-2-pyridones with improved <i>in vitro</i> antibacterial activity against fluoroquinolone resistant strains. Compounds <b>6o</b> and <b>6v</b> are representative of this class, targeting both bacterial DNA gyrase and topoisomerase IV (Topo IV). In an abbreviated susceptibility screen, compounds <b>6o</b> and <b>6v</b> showed improved MIC₉₀ values against <i>Escherichia coli</i> (0.5–1 μg/mL) and <i>Acinetobacter baumannii</i> (8–16 μg/mL) compared to the precursor compounds. In a murine septicemia model, both compounds showed complete protection in mice infected with a lethal dose of <i>E. coli</i>

Potent antimalarials with development potential identified by structure-guided computational optimization of a pyrrole-based dihydroorotate dehydrogenase inhibitor series

Dihydroorotate dehydrogenase (DHODH) has been clinically validated as a target for the development of new antimalarials. Experience with clinical candidate triazolopyrimidine DSM265 (1) suggested that DHODH inhibitors have great potential for use in prophylaxis, which represents an unmet need in the malaria drug discovery portfolio for endemic countries, particularly in areas of high transmission in Africa. We describe a structure-based computationally driven lead optimization program of a pyrrole-based series of DHODH inhibitors, leading to the discovery of two candidates for potential advancement to preclinical development. These compounds have improved physicochemical properties over prior series frontrunners and they show no time-dependent CYP inhibition, characteristic of earlier compounds. Frontrunners have potent antimalarial activity in vitro against blood and liver schizont stages and show good efficacy in Plasmodium falciparum SCID mouse models. They are equally active against P. falciparum and Plasmodium vivax field isolates and are selective for Plasmodium DHODHs versus mammalian enzymes