2 research outputs found
Diverse Heterocyclic Scaffolds as Allosteric Inhibitors of AKT
Wide-ranging exploration of potential replacements for
a quinoline-based
inhibitor of activation of AKT kinase led to number of alternative,
novel scaffolds with potentially improved potency and physicochemical
properties. Examples showed predictable DMPK properties, and one such
compound demonstrated pharmacodynamic knockdown of phosphorylation
of AKT and downstream biomarkers in vivo and inhibition of tumor growth
in a breast cancer xenograft model
Discovery of Imidazo[1,2‑<i>a</i>]pyridine Ethers and Squaramides as Selective and Potent Inhibitors of Mycobacterial Adenosine Triphosphate (ATP) Synthesis
The approval of bedaquiline
to treat tuberculosis has validated
adenosine triphosphate (ATP) synthase as an attractive target to kill Mycobacterium tuberculosis (Mtb). Herein, we report
the discovery of two diverse lead series imidazoÂ[1,2-<i>a</i>]Âpyridine ethers (IPE) and squaramides (SQA) as inhibitors of mycobacterial
ATP synthesis. Through medicinal chemistry exploration, we established
a robust structure–activity relationship of these two scaffolds,
resulting in nanomolar potencies in an ATP synthesis inhibition assay.
A biochemical deconvolution cascade suggested cytochrome c oxidase
as the potential target of IPE class of molecules, whereas characterization
of spontaneous resistant mutants of SQAs unambiguously identified
ATP synthase as its molecular target. Absence of cross resistance
against bedaquiline resistant mutants suggested a different binding
site for SQAs on ATP synthase. Furthermore, SQAs were found to be
noncytotoxic and demonstrated efficacy in a mouse model of tuberculosis
infection