Adavancing a novel chemotype for the treatment of multidrug-resistant cancer

Abstract

Effective cancer treatment is hindered by the onset of drug resistance, regardless of chemotherapeutic agent and its mechanism of action. Both intrinsic and acquired resistance may contribute to the limited efficacy of medicinal agents, presenting a serious challenge for the medical community, including patients, physicians, and scientists. To combat resistant malignancies, scientists have identified Bcl-2 family proteins as key regulators of programmed cell death and strategies to target key members of this family have become a focal point of drug discovery research. Such efforts by members of the Xing lab have led to the development of CXL017, an analogue of sHA 14-1 and novel lead for the treatment of drug-resistant cancers that overexpress antiapoptotic Bcl-2 family proteins. Investigation into the mechanism of action of CXL017 revealed unique biological activity, namely the ability to target several resistant cancer cell types, the ability to re-sensitize HL60/MX2, an acute myeloid leukemia multidrug-resistant cell line, to standard chemotherapeutic agents following long-term, sub-lethal treatment, and the ability to manipulate antiapoptotic Bcl-2 family proteins as well as SERCA, upon re-sensitization. These findings motivated further research regarding this series of compounds. Continued structure-activity relationship studies have led to the development of CXL070, the most advanced CXL to date. Herein, the synthesis and biological evaluation of ten CXL analogues leading to the discovery of CXL070 is reported. In addition, a detailed investigation into the inhibition of SERCA by CXL017 and structurally related analogues provides evidence of a unique binding site within the ER-Ca2+ pump. To gain insight into the exact binding site of CXLs within SERCA as well as enable the discovery of other potential cellular targets via a cell-based pull-down method, the synthesis and utility of a three bifunctional photoaffinity probes based on the CXL scaffold is presented. Preliminary experiments with purified protein and in cells support continued research based on this strategy. Collectively, this work supports the advancement of CXLs as a novel chemotype for the treatment of multidrug-resistant cancer.