**5.2 Mcl-1 inhibitors**

The anti-apoptotic protein myeloid cell leukemia-1 (Mcl-1) is an important regulator of apoptosis and a central driver of drug resistance in multitude of human malignancies. Overexpressed Mcl-1 imparts drug resistance of both solid tumors and hematological malignancies against various therapeutic agents. Several inhibitors have been developed that show promising anticancer activities in preclinical and clinical settings. For example S63845 induces apoptosis in SCLC cell lines in vitro at an IC50 of 23 to 78 nM, while in xenograft models this molecule causes significant reduction in tumor volumes. S63845 can be used in combination with navitoclax (a dual inhibitor of Bcl-xL and Bcl-2) where S63845 reduced the cell viability of SCLC cells and showed synergistic effects in S63845-resistant xenograft models [42]. Furthermore, Mcl-1 is an attractive drug target in lung cancer due to its non-apoptotic involvement in DNA repair. Thus targeting Mcl-1 with a small molecule inhibitor (MI-233) blocks Mcl-1-mediated HR DNA repair and thereby sensitizes cancer cells to treatment induced replication stress. MI-233 shows strong synergism with hydroxyurea or olaparib in lung cancer models [43]. Similarly, targeted Mcl-1 inhibition by RNAi also increases caspase-mediated cell death in cell models such as ERα + breast cancer cells [44]. A specific Mcl-1 inhibitor VU661013 induce tumor cell death and a causes synergistic reduction when used in combination with ABT-263 in tumor volume [45]. During the last several years, many Mcl-1 inhibitors have been developed. However, due to large surface-exposed hydrophobic BH3 binding groove, specific targeting of Mcl-1 poses a big challenge. Thus indirect targeting of Mcl-1 is emerging as important mechanism of action of alternative drug classes such as CDK9 inhibitors or deubiquitination inhibitors [46]. The pharmacological characteristics of the major Mcl-1 inhibitors are tabulated in **Table 3**.
