Wylie, Andrew, Schoepfer, Joseph, Jahnke, Wolfgang, Jacob, Sandra, Loo, Alice, Furet, Pascal, Marzinzik, Andreas, Pelle, Xavier, Donovan, Jerry, Zhu, Wenjing, Buonamici, Silvia, Hassan, Quamrul, Lombardo, Franco, Iyer, Varsha, Palmer, Michael, Berellini, Giuliano, Dodd, Stephanie, Thohan, Sanjeev, Bitter, Hans, Branford, Susan, Ross, David, Hughes, Timothy, Petruzzelli, Lilli, Vanasse, K. Gary, Warmuth, Markus, Hofmann, Francesco, Keen, Nicholas and Sellers, William (2017) The allosteric inhibitor ABL001 enables dual targeting of BCR-ABL1. Nature.

Abstract

Chronic myeloid leukaemia (CML) is driven by the activity of the BCR-ABL1 fusion oncoprotein. ABL1 kinase inhibitors have improved the clinical outcomes for patients with CML, with over 80% of patients treated with imatinib surviving for more than 10 years. Second-generation ABL1 kinase inhibitors induce more potent molecular responses in both previously untreated and imatinib-resistant patients with CML. Studies in patients with chronic-phase CML have shown that around 50% of patients who achieve and maintain undetectable BCR-ABL1 transcript levels for at least 2 years remain disease-free after the withdrawal of treatment. Here we characterize ABL001 (asciminib), a potent and selective allosteric ABL1 inhibitor that is undergoing clinical development testing in patients with CML and Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukaemia. In contrast to catalytic-site ABL1 kinase inhibitors, ABL001 binds to the myristoyl pocket of ABL1 and induces the formation of an inactive kinase conformation. ABL001 and second-generation catalytic inhibitors have similar cellular potencies but distinct patterns of resistance mutations, with genetic barcoding studies revealing pre-existing clonal populations with no shared resistance between ABL001 and the catalytic inhibitor nilotinib. Consistent with this profile, acquired resistance was observed with single-agent therapy in mice; however, the combination of ABL001 and nilotinib led to complete disease control and eradicated CML xenograft tumours without recurrence after the cessation of treatment.

Item Type:	Article
Date Deposited:	20 Apr 2017 00:45
Last Modified:	20 Apr 2017 00:45
URI:	https://oak.novartis.com/id/eprint/31301