BioCentury
ARTICLE | Distillery Therapeutics

Cancer

December 12, 2018 12:00 AM UTC

In vitro, cell culture and patient sample studies identified a SHP-2 inhibitor that could help treat myelomonocytic leukemia, B cell lymphoma and lung cancer. In silico screening of a small molecule library for compounds predicted to stabilize the inactive conformation of SHP-2, followed by chemical synthesis and in vitro binding and enzymatic activity assays of analogs of the screening hit, yielded a compound that bound wild-type SHP-2 with a Kd of 69 μM and inhibited the activity of wild-type and E67K gain-of-function mutant forms of the enzyme with IC50 values of 9.8 and 7.67 μM, respectively. In a mouse progenitor B cell lymphoma cell line, the compound decreased SHP-2 signaling and growth compared with vehicle. In human lung cancer cell lines, cells expressing the gain-of-function N58S SHP-2 mutant were more sensitive to the compound than cells expressing wild-type SHP-2. In myeloid blasts from a myelomonocytic leukemia patient harboring the E67K SHP-2 mutation, the compound decreased colony formation compared with vehicle. Next steps could include optimizing and testing the compound in animal models of myelomonocytic leukemia, B cell lymphoma and lung cancer.

Novartis AG has two SHP-2 inhibitors in development: TNO155 in Phase I testing to treat non-small cell lung cancer (NSCLC) and solid tumors, and SHP099 in preclinical testing to treat cancer...