Mcl-1 inhibitors

Treatment for myelodysplastic syndromes (MDS) remains insufficient due to clonal heterogeneity and lack of effective clinical therapies. While VEN response positively correlated with MDS with excess blasts, all MDS subtypes responded to MCL1 inhibition. Treatment with combined VEN+MCL1 inhibtion was synergistic in all MDS subtypes without significant injury to normal hematopoiesis and reduced MDS engraftment in MISTRG6 mice, supporting the pursuit of clinical trials with combined BCL2+MCL1 inhibition in MDS.

Furthermore, genetic knockdown or inhibition of EphA2 with the small molecule ALW-II-41-27 (ALW) reduces cancer cell growth in vitro and in vivo...To this end, TNBC lines MDA-MB-231, BT-549, HCC1395, and HCC1187 were seeded in 96-well plates and exposed to ALW alone or in combination with chemotherapeutic agents doxorubicin and paclitaxel, CDK inhibitor SCH-727965, and MCL-1 inhibitor S63845 and cell viability assessed by MTT assay at 48 hours...Furthermore, TUNEL assays show that addition of SCH-727965 to ALW significantly increases the induction of apoptosis by HCC1395 and HCC1187 cells. These preclinical studies demonstrate that combination of ALW and SCH-727965 potently reduces TNBC cell growth and promotes cell death, representing promising early data on the effects of EphA2 inhibition as part of a combination targeted therapeutic approach for triple-negative breast cancer.

Previous studies have demonstrated the importance of energy metabolism as it relates to numerous aspects of leukemia stem cell (LSC) biology. The presence of PTPN11 mutations represents both a novel method for predicting response to ven/aza and a potential strategy for targeting patients who progress. We propose that addition of an MCL-1 inhibitor for treatment of AML patients bearing PTPN11 or related mutations may increase therapeutic responses.