virtual screening followed by biochemical, biophysical, and cellular screening resulted in the identification of distinctly different TrkA kinase domain inhibitor scaffolds. X-ray structural analysis of representative inhibitors bound to TrkA kinase domain defined the binding mode and rationalized the mechanism of action. Preliminary assessment of the sub-type selectivity against the closest TrkB isoform, and early ADME guided the progression of select inhibitor leads in the screening cascade. The possibility of the actives sustaining to known TrkA resistance mutations assessed offers initial guidance into the required multiparametric lead optimization to arrive at a clinical candidate.
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| http://dx.doi.org/10.1039/c9md00554d | DOI Listing |
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