br Conformational control inhibition Conformational escape
Conformational control inhibition Conformational escape resistance is a phenomenon where point mutations (such as T315I) drive the Abl kinase toward the active type I state. “Switch-control inhibitors” bind in a non-ATP-competitive fashion to residues (E282, R386) the Abl protein uses to switch between inactive and active conformations. The lead clinical candidate, DCC-2036 (rebastinib), an orally active TKI, potently inhibits Abl by inducing and stabilizing an inactive, inhibitor-bound (type II) conformation, and retains efficacy against most clinically relevant CML-resistance mutants, including T315I, although “P loop” mutants (E255V, E255K) may be less sensitive. DCC-2036 inhibits Bcr-AblT315I-expressing cell lines, prolongs survival in mouse models of T315I-mutant CML and Ph+ ALL, and inhibits primary patient-derived leukemia aromatase inhibitors expressing T315I both in vitro and in vivo. Sustained inhibition of Bcr-Abl and downstream pathways was observed in patients with refractory CML enrolled on a phase I clinical trial of this agent. In a Ba/F3 cell-based mutagenesis screen, no BCR-ABL mutations emerged at higher concentrations of DCC-2036 that are readily achievable clinically. However, rebastinib is currently being developed as an inhibitor of the TRKA, TIE-2 and FLT3 kinases with a clinical focus on various solid tumors and refractory acute myelogenous leukemia.
Dual aurora/BCR-ABL kinase inhibitors The aurora kinases, which are overexpressed in many cancer types including leukemia, are serine-threonine kinases that regulate different steps during mitosis, including the G2-M transition, mitotic spindle organization, chromosome segregation, and cytokinesis. MK-0457 (VX-680) and KW-2449 potently inhibit both aurora and Bcr-Abl (including Bcr-AblT315I) kinases, but neither compound is any longer in clinical development. Other molecules in this category include XL228, PHA-739358, VE-465 and AT9283. AT9283 shows potent anti-proliferative activity on BCR-ABL+ cell lines and primary patient samples, both wild type and T315I, as well as in mouse xenograft models.
Combination strategies HDACIs potently enhance the lethality of the dual aurora/Bcr-Abl TKIs by interfering with the function of chaperone proteins such as heat shock protein 90 (hsp 90), of which Bcr-Abl is a client, and interruption of the mitotic spindle checkpoint (induction of “mitotic slippage”). Indeed, synergistic interactions have been demonstrated between MK-0457 (VX-680) and vorinostat, as well as between KW-2449 and entinostat, both in vitro and in vivo, in human BCR-ABL+ cells, including those resistant to imatinib and bearing the T315I and E255K mutations. Accordingly, a phase I clinical trial of AT9283 (which also inhibits fms-like tyrosine kinase 3 (FLT3) and Janus kinases) and entinostat in patients with relapsed/refractory and poor-risk acute leukemias will soon begin enrolling patients.
Conclusion In this very brief review, an attempt has been made to highlight some of the most promising strategies in development against the recalcitrant T315I “gatekeeper” mutation in BCR-ABL. Examples of other agents being studied include inhibitors of hsp 90 and RAC GTPases, protein phosphatase 2A activators, TKI/farnesyltransferase inhibitor combinations, the novel TKIs ON012380 (substrate-competitive) and HG-7-85-01 (ATP-competitive), and nilotinib combined with the allosteric inhibitor GNF-2. Although allogeneic transplantation had thus far been the only available therapeutic option for patients with the T315I mutation, this has finally begun to change.
Conflict of interest
Introduction GATA transcription factors contribute to the regulation of cell lineage commitment and differentiation. Although hematopoiesis is controlled by numerous transcription and signaling factors with tightly integrated functions, GATA1, GATA2 and GATA3 in the GATA family are involved in the developmental regulation of hematopoiesis. In addition to the essential role in normal hematopoiesis, recent studies demonstrated that mutation of GATA genes is involved in the development and progression of leukemia. p.L359V mutation of GATA2 gene was identified in about 10% of chronic myeloid leukemia (CML) cases at accelerated phase and myeloid blast crisis. Moreover, recent studies demonstrated that GATA2 gene mutations were identified in AML patients and in three different familial syndromes characterized by predisposition to myelodysplastic syndrome (MDS) and AML. These results collectively indicate that dysregulation of GATA2 might be involved in the development and/or progression of AML.