Designing Novel BCR-ABL Inhibitors for Chronic Myeloid Leukemia with Improved Cardiac Safety

Chronic myelogenous leukemia (CML) is a hematopoietic neoplastic disease that primarily results from the reciprocal translocation between chromosomes 9 and 22 (t9;22) (q34; q11) in a hematopoietic stem cell resulting in the formation of the bcr-abl oncogene. The advent of TKIs targeting the BCR-ABL oncogene represents an effective strategy for the treatment of CML or ALL since the fusion protein product of the Philadelphia chromosome (Ph), BCR-ABL, is linked to both CML and a subset of acute lymphoblastic leukemia (Ph+ ALL). Chronic myeloid leukemia (CML) and/or acute lymphoblastic leukemia can be effectively treated by developing tyrosine kinase inhibitors (TKIs) that target the BCR-ABL oncogene.

Imatinib (Gleevec), which selectively targets the ATP binding site of the BCR-ABL protein, was a first generation BCR-ABL tyrosine kinase inhibitor (TKI) that was approved two decades ago by the FDA for treating CML.  Initially, imatinib was found to increase the survival of CML patients, however, subsequent patients with advanced-stage CML experience relapse due to development of resistance and mutations. The second generation TKIs, Dasatinib, Nilotinib, and Bosutinib, have been shown to have efficacy in treating CML patients with certain BCR-ABL mutations, but not those with the T315I mutation which caused resistance to second-generation, Ponatinib, a third-generation TKI, has been demonstrated to be more efficacious in a number of mutations in the BCR-ABL protein, including  the “gatekeeper” T315I mutation, however, ponatinib has been reported to major limitation which is mainly significant adverse cardiovascular effects, notably serious venous thromboembolic events. Therefore, there is still the need to develop highly efficacious, safer and tolerable BCR-ABL inhibitors for the treatment of CML.

In a new research paper published in the Journal of Medicinal Chemistry, Oregon Health and Science University researchers Dr. Mallesh Pandrala, and Professor Sanjay Malhotra together with Dr. Arne Antoon Bruyneel, Dr. Anna Hnatiuk and Professor Mark Mercola at Stanford University tried to optimize a balance between treatment of the neoplasm and management of cardiovascular risk. They hypothesized that if a TKI were to be highly cardiac-safe especially in comparison to ponatinib and effective against both native and T315I mutant BCR-ABL, it would gain a broader scope of use and provide much-needed therapy to CML and Ph + ALL patients with T315I mutations. They postulated that by altering the structure of already-existing BCR-ABL inhibitors, they should be able to find a cardiac-safe BCR-ABL inhibitor. The authors tested the cardiotoxicity of the newly discovered molecules on human induced pluripotent stem cell-derived cardiomyocytes which share characteristics and functional properties of primary human heart tissue.

Their study clearly differentiated ponatinib’s undesirable cardiotoxicity and its desired anti-BCR-ABLT315I antitumor efficacy. Based on this knowledge, the research team successfully designed and produced several hybrid compounds that are more focused BCR-ABL inhibitors. The hybrids still exhibited strong inhibitory effects on K-562 human CML cells, including the toughest gatekeeper T315I mutant linked to CML disease progression. Both natural BCR-ABL and BCR-ABLT315I kinase activities were significantly inhibited by the most effective molecules which they named, 33a and 36a. On K-562 cells expressing BCRABLT315I, they also showed comparable efficacies and somewhat lessened potencies compared to those of ponatinib. The net enhanced safety was nonetheless significant in light of the 10-fold decreased potencies for in vitro inhibition of T315I mutant BCR-ABL. At all concentrations tested, compound 33a exhibited no cardiomyocyte or vascular toxicity. Researchers hypothesized that differential kinase inhibition may be a factor in why 33a and 36a are safer than ponatinib. Ponatinib inhibits a number of kinases that, at least in vitro, while 33a and 36a do not. Various kinase targeting may have different biological effects in vivo, which need to be investigated. Notably, the most cardiac-safe TKIs discovered to date were hybrids 33a and 36a. The authors reported the oral treatment of 33a and 36a resulted in a long-lasting tumor reduction in the K-562 xenograft model in mice. They may therefore be useful as promising lead molecules for developing a novel class of BCR-ABL inhibitors that may overcome cardiotoxicity and the T315I mutation.

The team concluded that the two compounds are the most cardiac-safe TKIs discovered to date, and they could be used to safely treat CML patients with the T315I mutation. The next step is to develop the compounds into potential drugs for the treatment of CML. The oral treatment of 33a and 36a resulted in a long-lasting tumor reduction in the K-562 xenograft model in mice. Thus, researchers believe that these compounds could be developed into a novel class of BCR-ABL inhibitors that overcome cardiotoxicity and the T315I mutation, potentially providing much-needed therapy to CML and Ph + ALL patients with T315I mutations.