molecules of the month

HTL22562 is a CGRP antagonist intended to treat acute migraines. Some prior oral CGRP antagonists failed in clinical trials due to liver tox. signals, so this program targeted a non-oral candidate with lower first-pass liver exposure that might avoid such issues. Impressively the authors were able to drive the program through structure-based design thanks to X-ray co-crystal structures with the CGRP ectodomain complex. Structure-guided programs have been rare for membrane-bound proteins like GPCRs due to the challenge in crystallizing relevant forms of these targets.