Dataset Information

Analysis of Flexibility and Hotspots in Bcl-xL and Mcl-1 Proteins for the Design of Selective Small-Molecule Inhibitors.

ABSTRACT: Although Bcl-xL and Mcl-1, two antideath Bcl-2 members, have similar, flexible binding sites, they can achieve high binding selectivity to endogenous binding partners and synthetic small-molecule inhibitors. Here, we employed molecular dynamic (MD) simulations and hotspot analysis to investigate the conformational flexibility of these proteins and their binding hotspots at the binding sites. Backbone flexibility analyses indicate that the highest degree of flexibility in Mcl-1 is the ?4 helical segment as opposed to the ?3 helix in Bcl-xL among four helical segments in their binding sites. Furthermore, common and unique binding hotspots at both proteins were identified using small-molecule probes. These analyses can aid the design of potent and specific small-molecule inhibitors for these proteins.

SUBMITTER: Yang CY

PROVIDER: S-EPMC4025761 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature

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Analysis of Flexibility and Hotspots in Bcl-xL and Mcl-1 Proteins for the Design of Selective Small-Molecule Inhibitors.

Yang Chao-Yie CY Wang Shaomeng S

ACS medicinal chemistry letters 20120229 4

Although Bcl-xL and Mcl-1, two antideath Bcl-2 members, have similar, flexible binding sites, they can achieve high binding selectivity to endogenous binding partners and synthetic small-molecule inhibitors. Here, we employed molecular dynamic (MD) simulations and hotspot analysis to investigate the conformational flexibility of these proteins and their binding hotspots at the binding sites. Backbone flexibility analyses indicate that the highest degree of flexibility in Mcl-1 is the α4 helical ...[more]

PMID: 24900469

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Project description:Development of resistance to chemo- and radiotherapy in patients suffering from advanced cervical cancer narrows the therapeutic window for conventional therapies. Previously we reported that a combination of the selective BCL-2 family inhibitors ABT-263 and A-1210477 decreased cell proliferation in C33A, SiHa and CaSki human cervical cancer cell lines. As ABT-263 binds to both BCL-2 and BCL-XL with high affinity, it was unclear whether the synergism of the drug combination was driven either by singly inhibiting BCL-2 or BCL-XL, or inhibition of both. In this present study, we used the BCL-2 selective inhibitor ABT-199 and the BCL-XL selective inhibitor A1331852 to resolve the individual antitumor activities of ABT-263 into BCL-2 and BCL-XL dependent mechanisms. A-1210477 was substituted for the orally bioavailable S63845. Four cervical cancer cell lines were treated with the selective BCL-2 family inhibitors ABT-199, A1331852 and S63845 alone and in combination using 2-dimensional (2D) and 3-dimensional (3D) cell culture models. The SiHa, C33A and CaSki cell lines were resistant to single agent treatment of all three drugs, suggesting that none of the BCL-2 family of proteins mediate survival of the cells in isolation. HeLa cells were resistant to single agent treatment of ABT-199 and A1331852 but were sensitive to S63845 indicating that they depend on MCL-1 for survival. Co-inhibition of BCL-2 and MCL-1 with ABT-199 and S63845, inhibited cell proliferation of all cancer cell lines, except SiHa. However, the effect of the combination was not as pronounced as combination of A1331852 and S63845. Co-inhibition of BCL-XL and MCL-1 with A1331852 and S63845 significantly inhibited cell proliferation of all four cell lines. Similar data were obtained with 3-dimensional spheroid cell culture models generated from two cervical cancer cell lines in vitro. Treatment with a combination of A1331852 and S63845 resulted in inhibition of growth and invasion of the 3D spheroids. Collectively, our data demonstrate that the combination of MCL-1-selective inhibitors with either selective inhibitors of either BCL-XL or BCL-2 may be potentially useful as treatment strategies for the management of cervical cancer.

Project description:An estimated 40,000 deaths will be attributed to breast cancer in 2016, underscoring the need for improved therapies. Evading cell death is a major hallmark of cancer, driving tumor progression and therapeutic resistance. To evade apoptosis, cancers use antiapoptotic Bcl-2 proteins to bind to and neutralize apoptotic activators, such as Bim. Investigation of antiapoptotic Bcl-2 family members in clinical breast cancer datasets revealed greater expression and more frequent gene amplification of MCL1 as compared with BCL2 or BCL2L1 (Bcl-xL) across three major molecular breast cancer subtypes, Luminal (A and B), HER2-enriched, and Basal-like. While Mcl-1 protein expression was elevated in estrogen receptor α (ERα)-positive and ERα-negative tumors as compared with normal breast, Mcl-1 staining was higher in ERα+ tumors. Targeted Mcl-1 blockade using RNAi increased caspase-mediated cell death in ERα+ breast cancer cells, resulting in sustained growth inhibition. In contrast, combined blockade of Bcl-2 and Bcl-xL only transiently induced apoptosis, as cells rapidly acclimated through Mcl-1 upregulation and enhanced Mcl-1 activity, as measured in situ using Mcl-1/Bim proximity ligation assays. Importantly, MCL1 gene expression levels correlated inversely with sensitivity to pharmacologic Bcl-2/Bcl-xL inhibition in luminal breast cancer cells, whereas no relationship was seen between the gene expression of BCL2 or BCL2L1 and sensitivity to Bcl-2/Bcl-xL inhibition. These results demonstrate that breast cancers rapidly deploy Mcl-1 to promote cell survival, particularly when challenged with blockade of other Bcl-2 family members, warranting the continued development of Mcl-1-selective inhibitors for targeted tumor cell killing.Implications: Mcl-1 levels predict breast cancer response to inhibitors targeting other Bcl-2 family members, and demonstrate the key role played by Mcl-1 in resistance to this drug class. Mol Cancer Res; 15(3); 259-68. ©2016 AACR.

Dataset Information

Analysis of Flexibility and Hotspots in Bcl-xL and Mcl-1 Proteins for the Design of Selective Small-Molecule Inhibitors.

Publications

Analysis of Flexibility and Hotspots in Bcl-xL and Mcl-1 Proteins for the Design of Selective Small-Molecule Inhibitors.

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