Inhibitors of ABL and the ABL-T315I Mutation

Abstract

Chronic myelogenous leukemia (CML) is a hematological stem cell disorder caused by increased and unregulated growth of myeloid cells in the bone marrow, and the accumulation of excessive white blood cells. Abelson tyrosine kinase (ABL) is a non-receptor tyrosine kinase involved in cell growth and proliferation and is usually under tight control. However, 95% of CML patients have the ABL gene from chromosome 9 fused with the breakpoint cluster (BCR) gene from chromosome 22, resulting in a short chromosome known as the Philadelphia chromosome. This Philadelphia chromosome is responsible for the production of BCR-ABL, a constitutively active tyrosine kinase that causes uncontrolled cellular proliferation. An ABL inhibitor, imatinib, was approved by the FDA for the treatment of CML, and is currently used as first line therapy. However, a high percentage of clinical relapse has been observed due to long term treatment with imatinib. A majority of these relapsed patients have several point mutations at and around the ATP binding pocket of the ABL kinase domain in BCR-ABL. In order to address the resistance of mutated BCR-ABL to imatinib, 2(nd) generation inhibitors such as dasatinib, and nilotinib were developed. These compounds were approved for the treatment of CML patients who are resistant to imatinib. All of the BCR-ABL mutants are inhibited by the 2(nd) generation inhibitors with the exception of the T315I mutant. Several 3(rd) generation inhibitors such as AP24534, VX-680 (MK-0457), PHA-739358, PPY-A, XL-228, SGX-70393, FTY720 and TG101113 are being developed to target the T315I mutation. The early results from these compounds are encouraging and it is anticipated that physicians will have additional drugs at their disposal for the treatment of patients with the mutated BCR-ABL-T315I. The success of these inhibitors has greater implication not only in CML, but also in other diseases driven by kinases where the mutated gatekeeper residue plays a major role.

Chronic Myeloid Leukemia Stem Cells

“…Molecular mechanisms that promote CML progenitor survival such as bcl-2; self-renewal such as sonic hedgehog, bmi-1, notch and Wnt; and block differentiation such as JAK2/STAT5 activation and HOX gene hypermethylation may be targeted effectively using combinations of small molecule inhibitors and demethylating agents. [90][91][92][93][94][95][96][97][98][99][100][101] Notably, a plethora of bcl-2 family member inhibitors are currently under development, JAK2/ STAT5 inhibitors are currently being tested in clinical trials and self-renewal pathway inhibitors such as gammasecretase inhibitors have been used clinically albeit with gastrointestinal toxicity. Although Wnt and sonic hedgehog inhibitors are still being evaluated in preclinical models, they hold great promise clinically for eradicating committed progenitors that have aberrantly gained self-renewal capacity as a result of oncogenic addiction to one of these pathways.…”

Benzo[e]pyridoindoles, novel inhibitors of the Aurora kinases

“…VX-680, considered as the Aurora reference inhibitor, suppresses tumor growth in vivo and encouraging results were reported for three patients with refractory Chronic Myeloid Leukemia 21,22 perhaps partly through the inhibition of the T315I mutant BCR-ABL. 23 The in vitro high throughput screening of the proprietary Institut Curie-CNRS small molecule library of 6560 compounds allowed the identification of benzo[e]pyridoindoles as new inhibitors of Aurora kinases. Ex vivo assays in HeLa cells showed that the identified best hit (compound 1, C1) inhibited the activity of Aurora B and mimicked the phenotype obtained after siRNA suppression of Aurora B expression.…”

Homoharringtonine, omacetaxine mepesuccinate, and chronic myeloid leukemia circa 2009

“…Various agents have demonstrated activity in vitro against the T315I mutation, and some of them currently are under development in clinical trials (eg, AP24534, PHA-739358, PPY-A, XL-228, SGX-70,393, FTY720, TG101113, and KW-2449). [74][75][76] These drugs are all in phase 1 development stages and results are eagerly awaited. The promising results reported with omacetaxine mepesuccinate in this setting favor the notion of this drug as a viable option for the treatment of patients who carry the T315I mutation, particularly in those for whom stem cell transplantation is not an option.…”