Preclinical Studies of the Pathogenesis and Therapy of Ph+ Leukemia in Mice: A Critical Role for Gab2 and Development of a Novel Inhibitor of ABL T315I.
Chan, Wayne.
2012
-
Abstract: Dysregulated tyrosine kinases (TKs) are the hallmark of nearly all cases of myeloproliferative neoplasms (MPNs). The most widely studied of these TKs is BCR-ABL1, a known direct molecular cause of both CML and Ph+ B-ALL. The cardinal role of BCR-ABL1 in the pathogenesis of CML came from the development of a bone marrow transduction/transplantation mouse model, in which retrovirally-direc... read moreted expression of only BCR-ABL1 led to an MPN myeloproliferative disease that shared many of the features of the human disease. This observation and other studies led to the development of imatinib mesylate, a small molecule inhibitor of the ABL1 TK that has a long track record of inducing hematologic and cytogenetic remissions in CML-CP patients in the chronic phase of their disease. Despite the unquestioned success of imatinib and other second generation TKIs in the treatment of CML, they present emerging clinical challenges. One strategy to address the challenge of imatinib resistance is to seek a better understanding of the molecular pathogenesis of CML. Previous work in our laboratory has led to the identification of Tyr177 phosphorylation, and recruitment of the GRBrb2 adaptor protein, as absolutely critical steps in the development of CML. Further in vitro work has implicated the importance of a GRBrb2/GABab2 interaction in BCR-ABL1- mediated transformation. In particular, genetic experiments in the context of the mouse model of leukemogenesis were used to assess the importance of GABab2 in both CML and Ph+ B-ALL. The most common mechanism for imatinib resistance involves point mutations in the kinase domain of BCR-ABL1 that alter or disrupt inhibitor binding. The kinase domain mutations that confer drug resistance have been previously described. The development of second generation TKIs have focused largely on rational design of drugs that bind within the kinase domain. As a result, these second-line therapies have had some success in treating imatinib- resistant CML, but several mutations, in particular the BCR-ABL1 T315I mutation, confer resistance to all approved drugs. We present current work taking a different approach to the rational design of TKIs. In particular, we will describe the pre-clinical development of a family of TKIs called switch pocket inhibitors. The small molecule inhibitors are non-ATP competitive inhibitors that function by stabilizing the inactive form of the BCR-ABL1 tyrosine kinase.
Thesis (Ph.D.)--Tufts University, 2012.
Submitted to the Dept. of Cellular & Molecular Physiology.
Advisor: Richard Van Etten.
Committee: Brent Cochran, Daniel Jay, and George Daley.
Keywords: Biology, and Physiology.read less - ID:
- cj82kk77n
- Component ID:
- tufts:20281
- To Cite:
- DCA Citation Guide EndNote
