**4.2 The role of BH3-mimetics as a potential therapeutic option for cancer**

Bcl-2 family proteins control the intrinsic apoptosis pathway toward protein– protein interactions, which including all BH-3 domains [141, 142]. Currently, the therapeutic approaches mostly focused on mimicking and target the BH-3 only proteins. BH-3 mimetics are small molecule compounds and bind to anti-apoptotic Bcl-2 proteins. Therefore, inhibit their activity and promotes apoptosis [133, 143]. Of note, BH-3 mimetics can start apoptosis by leading to activation of Bax/Bak or by inhibiting anti-apoptotic Bcl-2 family proteins [142]. Between a variety of BH-3 mimetics that have been generated, ABT-737 and ABT-263 (Navitoclax) showed the most promising antitumor efficacy by engaging anti-apoptotic Bcl-2 family proteins. Both drugs are shown to engage to Bcl-2, Bcl-Xl, and Bcl-w. Somehow, the use of Navitoclax showed to cause thrombocytopenia by inhibition of Bcl-xl, as a major adverse effect [144, 145]. These side effects lead to exclusion of Navitoclax as an effective chemotherapeutic drug and required new findings more selective for Bcl-2 inhibitors, so can induce cell death without causing critical side effects. Indeed, ABT-199 (Navitoclax) was subsequently developed to replace Navitoclax, as a highly selective Bcl-2 inhibitor. Venetoclax binds with high affinity to Bcl-2 and a lesser extent to other Bcl-2 family proteins including Bcl-xl and Bcl-w. Also, Venetoclax lacks off-target effects on BCL-XL [146]. Altogether, the pre-clinical experience with venetoclax and together with combining BCR signaling inhibitors were shown to be very promising with significant efficacy in the patient population Chronic Lymphocytic Leukemia (CLL) and Diffuse Large B-cell Lymphoma (DLBCL). The study by Binu Sasi et al., in 2019, showed that fostamatinib and ibrutinib can sensitize DLBCL cell lines to venetoclax, which marks the importance of combination approaches. In conclusion, the findings provided a rational explanation for testing the use of combination therapy with venetoclax and selective BCR inhibitors in clinical use in DLBCL [147]. The progress of research is underlying the continuous role of Bcl-2 family inhibitors as promising and effective anticancer therapeutic agent. However, another small molecule BDA-366 (BH4 domain inhibitor) is also recently described as a promising approach in anticancer treatment. The potent effects of BDA-366 have been experimentally validated in both in vitro and in vivo, by showing significant anticancer activity [148]. Lastly, a very innovative strategy again comes from Bcl-2, the Bcl-2 gene is known to be rich with GC sequence which is placed in the promoter region, and has the potential to form G-quadruplex structures. Thus, is playing a role as a transcriptional repressor element and these G-quadruplex-specific ligands are capable of regulating Bcl-2 transcriptionally [149, 150].
