py. A phase III study for ponatinib in first-line therapy is in the planning Dipeptidyl peptidase-4 stage. Aurora kinases are serine/threonine kinases known to regulate mitosis.82 Due to their role in cell cycle progression and the fact that they are overexpressed in leukemias and solid tumors,83 aurora kinases make attractive targets in CML therapeutic development. Several compounds with activity against ABL mutants, including T315I were developed and entered clinical trials. Among these, the most tested candidate is AT9283 with activity against ABL, as well as Aurora A/B kinases, and Janus kinases 2/3.84 Preclinical efficacy was demonstrated in mouse models leading to initiation of clinical trials.84 Phase I and IIa clinical trials were completed in October 2010, and a recommended phase II dose was determined.
Danusertib, another Aurora kinase inhibitor is currently in phase I studies in patients with refractory Ph+ leukemias.85 Results have not yet been published. ETA-receptor cancer Two other Aurora kinase inhibitors with activity against T315I mutant ABL, MK-0457 and XL228, failed in clinical trials for various reasons, including toxicity.86 The clinical efficacy of compounds inactive against Woessner et al. Page 6 Cancer J. Author manuscript, available in PMC 2012 May 1. NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript T315I, but which inhibit other pathways remains to be determined. Table 1 provides an overview of new compounds in development for Ph+ leukemias. Allosteric/non-ATP Competitive Inhibitors DCC-2036 is an inhibitor of BCR-ABL that forces a conformational change of ABL upon drug binding.
ABL can exist in either an active or inactive conformation based on phosphorylation status. Structure-based design of DCC-2036 elucidated a switch-pocket in ABL, inducing a stable and inactive state.87 DCC-2036 inhibits ABL in a non-ATP competitive manner, it also inhibits Src, Lyn, Fgr, Hck, Flt3, and Tie2, but spares Kit. Based on efficacy in pre-clinical studies, a phase I trial has been initiated and is currently recruiting. An allosteric, non-ATP competitive inhibitor of BCR-ABL is GNF-2 , which was discovered during kinase activity screening.88 GNF-2 is hypothesized to bind at the myristoyl binding cleft of BCR-ABL, distant from the active site of BCR-ABL. GNF-2 has exceptional specificity for BCR-ABL, does not inhibit c-Kit, PDGFR, or other kinases , and is non-toxic towards non-BCR-ABL expressing cells.
88 GNF-2 has been found to enhance imatinib activity against BCR-ABL, while a GNF-2 analog was found to synergize with dasatinib against the T315I mutant.89 Other GNF analogues are in development90,91 but none are currently in clinical trials. The Essential BCR Coiled-Coil Oligomerization of BCR-ABL through the coiled-coil domain is essential for oncogenicity,92,93 making this region an attractive target for therapeutic development.94 Non-small molecule inhibitors targeting the BCR coiled-coil are exciting alternatives that disrupt BCR-ABL oligomerization and activation. We have recently reported the disruption of BCR-ABL via a rationally designed mutant coiled-coil peptide.
95 Such peptides may reduce the risk of acquired resistance due to the numerous contact points between the coiledcoil and the protein, or because peptides are not typical substrates for drug efflux transporters whose overexpression may lead to resistance.85 Delivery strategies for peptide therapeutics to the CML cell are a current focus of our lab. Degrading BCR-ABL A natural compound in vegetables, PEITC, was found to kill T315I harboring cells in culture and from patient samples.96 PEITC induces oxidative stress in CML cells leading to degradation of BCR-ABL. Another degradation strategy involves a novel ubiquitin-cycle inhibitor, WP1130, reported to ra