Anti-cancer drug discovery and development

Abstract

Deregulated apoptosis is a hallmark of cancer, and the B-cell lymphoma-2 (Bcl-2) family of proteins is pivotal to mediating the intrinsic pathway of this process. Recent advances have yielded both pan-Bcl-2 small molecule inhibitors (SMIs) that inhibit both the Bcl-2 and the Mcl-1 arm of the Bcl-2 family anti-apoptotic proteins, as well as selective SMIs to differentially target the two arms. Of these SMIs, ABT-263 (navitoclax), AT-101 [(-)-gossypol], and obatoclax (GX15-070) are currently in clinical trials for multiple cancers. While pan-Bcl-2 inhibitors such as AT-101 and obatoclax can be more toxic for inhibiting all members of the anti-apoptotic Bcl-2 family of proteins, resistance can quickly develop for ABT-263, a selective Bcl-2 inhibitor. In this article, we discuss the current status of Bcl-2 family SMIs in preclinical and clinical development. As Mcl-1 upregulation is a major mechanism of ABT-263 resistance, Mcl-1-specific inhibitors are expected to be efficacious both in combination/sequential treatments and as a single agent against cancers resistant to ABT-263.

Identifying the druggable interactome of EWS-FLI1 reveals MCL-1 dependent differential sensitivities of Ewing sarcoma cells to apoptosis inducers

“…Next, we studied the mechanism behind the EWS-FLI1 dependent differential response to the tested BCL-2 family inhibitors. Although the target profiles of obatoclax and navitoclax were similar, affinities and the selectivity for the anti-apoptotic BCL-2 family members differed dramatically [ 22 ]. Navitoclax, like ABT-737, shows strong affinity for BCL-2, BCL-X(L), and BCL-W, while they are inactive towards MCL-1 and BCL-B.…”

Nanotechnology inspired tools for mitochondrial dysfunction related diseases

“…The BCl-2 homology 3 (BH3) protein preferentially binds to BCl-2 through its homology domain and neutralizes its activity to induce apoptosis (66, 67). Small molecules mimicking the topology of BH3, referred as BH3 mimics, can bind and deactivate the function of pro-apoptotic BCl-2 and serve as promising drug candidates (68–70). BH3 mimetic small molecules, ABT-737, ABT-263, gossypol, AT-101, and alpha-tocopheryl succinate ( α -TOS) along with other chemotherapeutics, show promising selectivity in targeting pro-apoptotic proteins and increased efficacy (71, 72).…”

CT Perfusion Can Predict Overexpression of CXCL8 (Interleukin-8) in Head and Neck Squamous Cell Carcinoma

“…12 Previous investigators have shown that tumors cannot expand greater than 1-2mm in size without the induction of angiogenesis. 13 Three of the primary activators of angiogenesis which promote endothelial proliferation are vascular endothelial growth factor (VEGF), CXCL1 (growth-related oncogene, GRO-alpha), and CXCL8 (interleukin-8). 13,14 The expression of CXCL8 is activated by the NF-kappaB signaling pathway which is controlled by a pro-angiogenic signaling molecule, Bcl-2.…”

“…13 Three of the primary activators of angiogenesis which promote endothelial proliferation are vascular endothelial growth factor (VEGF), CXCL1 (growth-related oncogene, GRO-alpha), and CXCL8 (interleukin-8). 13,14 The expression of CXCL8 is activated by the NF-kappaB signaling pathway which is controlled by a pro-angiogenic signaling molecule, Bcl-2. 16 Recent studies have shown that Bcl-2 is substantially upregulated in HNSCC compared to normal oral mucosal endothelial cells, which would suggest that that HNSCC may have elevated levels of CXCL8.…”