Aberrant activation of the Hedgehog (Hh) pathway has been associated with numerous malignancies including basal cell carcinoma, medulloblastoma, and pancreatic cancer. Several reports also suggest that positive regulators of the Hh pathway could be used in the treatment of neurodegenerative diseases.
Chemical Diversity has been working in collaboration with Dr. James Chen of Stanford University, on the design and evaluation of compound libraries for Hh pathway screens. Previous efforts to identify Hh pathway regulators have resulted in numerous inhibitors of the signaling protein Smoothened, a 7-TM component of the pathway. In order to identify other "druggable" targets within the pathway, we have focused our efforts on the discovery of mechanistically distinct antagonists using an NIH-3T3 cell-based assay. We have now screened an initial set of 3,000 compounds that broadly sample chemical diversity space and found several potential antagonists. Secondary screens to confirm these 'hits' and epistatically link them to known Hh pathway components are ongoing, and these studies will guide the assembly of second-generation libraries for lead optimization. Particular attention has been paid to i) IP potential, ii) synthetic feasibility, iii) drug-like potential and iv) activity profile of the identified templates.
This ongoing collaboration have produced very promising results that will enable Chemical Diversity to design new systems of functional libraries for efficient screening in multiple bioassay formats. This collaboration is a beautiful example of synergy between excellent biological and medicinal chemistry expertise of the Stanford and Chemical Diversity teams.