molecules of the year

July’s molecule, the AbbVie BCL-XL inhibitor A-1331852, is a highly potent, orally bioavailable, protein-protein interaction inhibitor which triggers tumor cell apoptosis. The molecule emerged from a long, challenging fragment-assisted discovery campaign, as might be expected for a formerly “undruggable” target. The compound was an important tool compound for understanding the on-target biology of BCL-family protein inhibitors (particularly with respect to heme toxicities), and ultimately led to the development of a safer antibody-drug conjugate (ABBV-155) which recently entered Ph. I studies for solid tumors. Impressively, it was the AbbVie chemistry team that pushed to successfully continue the BCL-XL program with a biologic modality.