Development of a chemical probe targeting lemur tyrosine kinase 3 for Breast Cancer treatment and to reduce resistance to current drugs

Abstract

Breast Cancer is the most common among women. There are some therapies being used, however the high degree of heterogenicity makes it necessary the search for new targets and drugs. The Lemur Tyrosine Kinase 3 (LMTK3) was found in a silencing RNA screening as a promising target for this disease. It is an estrogen receptor modulator and it inhibition has antitumoral effects even against triple-negative Breast Cancer cells (most lethal). This kinase is also involved in resistance mechanisms for current Cancer drug. In this work we will search for a potent and selective inhibitor for LMTK3. It will be done a structure-activity relationship analysis for the generation of inhibitors analogues, with the results being followed by enzymatic inhibition assays. Most promising candidates will be tested in NanoBRET assay to evaluate it intracellular binding and potency. This structure-activity relationship will be guided by co-crystal structure of LMTK3 kinase domain with the inhibitor candidates. To study effects inside the cell it will be done functional assays with 3 different Breast Cancer cell line: MCF7, MDA-MB-231 and BT-474. As LMTK3 is a modulator of resistance to the Cancer treatment with tamoxifen and doxorubicin, we will test combined therapy with these drugs and our inhibitors in order to reduce drug resistance. At last, to better understand the cellular mechanisms that happens with LMTK3 inhibition, we will analyze using BioID how the protein interaction network of this kinase is affected with the addition of our inhibitor. (AU)