Despite imatinib’s impressive milestones in CML and the success of the second-generation tyrosine kinase (TK) inhibitors dasatinib and nilotinib in circumventing the majority of BCR-ABL resistance mutations, CML is still standing, albeit wobbly-kneed. With a frequency of ~15 percent among resistance mutations, the common ABL1T315I gatekeeper mutation exhibits pan-resistance to all of the currently approved TK inhibitors and has remained one major obstacle to vanquishing CML. From a clinical and drug development perspective, this challenge has carried the tonal equivalent to what Apollo Creed must have thought about Rocky Balboa in their first epic 15-round match: What is it going to take to knock this guy out?
Secondary resistance to TK inhibitors mediated by mutations such as ABL1T315I either impede drug binding due to steric hindrance in the ATP binding pocket (e.g., dasatinib) or result in a switch from the type II inactive to type I active conformation of the kinase to which these drugs can no longer bind (e.g., imatinib and nilotinib). This latter form of resistance, referred to as “conformational escape” is mediated by specific “switch control” amino acid residues within ABL1 that adopt orientations between the type I phosphorylated and type II unphosphorylated states. In this elegant report, collaborators from Tufts Medical Center, Emerald Biostructures, and Deciphera Pharmaceuticals used structural-based design to optimize development of a “switch control inhibitor” designed to interact with these critical residues in order to achieve a stable, inactive conformation state even in the presence of resistance mutations. These aims were realized by a series of synthetic maneuvers that culminated in the development of compound DCC-2036 with docking sites to both the switch control pocket (amino acids E282/R386) and the ATP hinge region of ABL1.
DCC-2036 exhibits an IC50 of 0.8 nM for ABL1 and 4 nM for ABL1T315I and exhibits low nanomolar inhibitory activity against SRC family of kinases, FLT3, and TIE2. In comparison, the IC50 for ABL1T315I for imatinib, dasatinib, and nilotinib range from 3,800 to more than 10,000 nM. Pre-clinical data indicate that DCC-2036 inhibits the proliferation of Ba/F3 cells transformed by BCR-ABL1T315I and downstream signaling effectors such as STAT5 and CrkL. In mice engrafted with BCR-ABL1T315I -transformed Ba/F3 cells or in a retroviral transduction/transplantation model of BCR-ABL1T315I-induced CML and B-cell ALL, DCC-2036 significantly prolonged survival compared with imatinib or dasatinib. DCC-2036 inhibited marrow-derived myeloid colonies from patients with either chronicphase or relapsed accelerated-phase CML (with little effect on normal marrow cells) and inhibited BCR-ABL kinase activity and CrkL phosphorylation in patients with BCR-ABL1T315I -positive B-cell ALL and chronic-phase CML with the L298V mutation.
In Brief
A phase I clinical trial with DCC-2036 is currently underway to assess its safety and efficacy in patients with Ph+ CML or ALL that 1) exhibit the BCR-ABL1T315I mutation or 2) exhibit resistance or intolerance to ≥ 2 TKIs with known efficacy. DCC-2036 joins AP24534 (ponatinib) as a novel agent with different mechanisms of action focused on T315I-resistant disease. Although it is anticipated that these TKs will have a major impact on this disease population, nature has repeatedly shown that it will not easily surrender to the 10-count and fall to the canvas; resistance in some form is almost assured.
Competing Interests
Dr. Gotlib indicated no relevant conflicts of interest.&
