Novel Small-Molecule Inhibitors of Bcl-XL to Treat Lung Cancer

Abstract

Bcl-XL is a major anti-apoptotic protein in the Bcl-2 family whose overexpression is more widely observed in human lung cancer cells than that of Bcl-2, suggesting that Bcl-XL is more biologically relevant and therefore a better therapeutic target for lung cancer. Here, we screened small molecules that selectively target the BH3 domain (aa 90–98) binding pocket of Bcl-XL using the UCSF DOCK 6.1 program suite and the NCI chemical library database. We identified two new Bcl-XL inhibitors (BXI-61 and BXI-72) that exhibit selective toxicity against lung cancer cells compared with normal human bronchial epithelial cells. Fluorescence polarization assay reveals that BXI-61 and BXI-72 preferentially bind to Bcl-XL protein but not Bcl2, Bcl-w, Bfl-1/A1 or Mcl-1 in vitro with high binding affinities. Treatment of cells with BXI-72 results in disruption of Bcl-XL/Bak or Bcl-XL/Bax interaction, oligomerization of Bak and cytochrome c release from mitochondria. Importantly, BXI-61 and BXI-72 exhibit more potent efficacy against human lung cancer than ABT-737 but less degree in platelet reduction in vivo. BXI-72 overcomes acquired radioresistance of lung cancer. Based on our findings, the development of BXI(s) as a new class of anticancer agents is warranted and represents a novel strategy for improving lung cancer outcome.

Brassinin inhibits STAT3 signaling pathway through modulation of PIAS-3 and SOCS-3 expression and sensitizes human lung cancer xenograft in nude mice to paclitaxel

“…We also found that BSN significantly inhibited tumor cell invasion activity in A549 cells, which may be explained by its ability to negatively regulate the expression of MMP-9 and COX-2 proteins. Bcl-2 and Bcl-xl expression are mainly regulated by STAT3 pathway, and these proteins are overexpressed in lung cancer cells [50, 51]. The downregulation of Bcl-2, Bcl-xl and survivin proteins could account for BSN's ability to induce substantial apoptosis in A549 cells.…”

Bcl-2 family of proteins as drug targets for cancer chemotherapy: the long way of BH3 mimetics from bench to bedside

“…Hence, a new Bcl-X L potent inhibitor, A-1155463, has been recently developed using structure-based design which has already shown in vivo activity [57]. Two other Bcl-X L specific inhibitors have shown to be active against lung cancer cells [58]. Importantly, these compounds caused less effect than ABT-737 on platelet reduction.…”

Targeting KRAS-mutant non-small cell lung cancer: challenges and opportunities

“…By also giving the BCL-XL inhibitor ABT-263, the inhibitory effect on Bim was abrogated and robust apoptosis was observed [55]. Since ABT-263 was found to cause Grade III and IV thrombocytopenia in 41% of patients in a recent Phase II study of small cell lung cancer [56], we developed a novel BCL-XL inhibitor, which is more potent but induces much less toxicity [57] and is currently in testing. Similarly, using a kinome-centered synthetic lethality screen, Sun et al [31] found that targeting HER3 may act synergistically with MEK inhibition in KRAS-mutant cancers including NSCLC.…”