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Synthetic inhibitor leads of human tropomyosin receptor kinase A (hTrkA)

DOI: 10.1039/C9MD00554D DOI Help

Authors: Govindan Subramanian (Zoetis) , Rajendran Vairagoundar (Zoetis) , Scott J. Bowen (Zoetis) , Nicole Roush (Zoetis) , Theresa Zachary (Zoetis) , Christopher Javens (Zoetis) , Tracey Williams (Zoetis) , Ann Janssen (Zoetis) , Andrea Gonzales (Zoetis)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Rsc Medicinal Chemistry , VOL 298

State: Published (Approved)
Published: January 2020

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

Subject Areas: Chemistry, Biology and Bio-materials, Medicine


Instruments: I02-Macromolecular Crystallography

Added On: 26/02/2020 10:51

Discipline Tags:

Health & Wellbeing Biochemistry Chemistry Structural biology Organic Chemistry Biophysics Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)