Discovery and Characterization of 2,5-Substituted Benzoic Acid Dual Inhibitors of the Anti-apoptotic Mcl-1 and Bfl-1 Proteins

Kump, Karson J.; Miao, Lei; Mady, Ahmed S.A.; Ansari, Nurul H.; Shrestha, Uttar K.; Yang, Yuting; Pal, M.; Liao, Chenzhong; Perdih, Andrej; Abulwerdi, Fardokht A.; Chinnaswamy, Krishnapriya; Meagher, Jennifer L.; Carlson, Jacob M.; Khanna, May; Stuckey, Jeanne A.; Nikolovska‐Coleska, Zaneta

doi:10.1021/acs.jmedchem.9b01442

Cited by 31 publications

(16 citation statements)

References 72 publications

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“…These include S64315/MIK665 (71), AZD-5991 (72), PRT1419 (73), and AMG-176 (74), among others, which are currently being explored in clinical trials (NCT02992483, NCT04629443, NCT03013998, NCT02675452, NCT04178902, NCT04543305, and others), mostly in hematologic malignancies. Other compounds that inhibit or degrade MCL1 have also demonstrated activity in preclinical models (75)(76)(77)(78). Given that MCL1 is a shortlived protein (79), indirect targeting by CDK9 inhibitors, such as alvocidib, AZD4573 (NCT03263637), or voruciclib (NCT03547115), or protein selective degradation approaches (75) have emerged as alternative strategies (80).…”

Section: Reviewmentioning

confidence: 99%

Adapted to Survive: Targeting Cancer Cells with BH3 Mimetics

Montero

Haq

2022

Cancer Discovery

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A hallmark of cancer is cell death evasion, underlying suboptimal responses to chemotherapy, targeted agents, and immunotherapies. The approval of the antiapoptotic BCL2 antagonist venetoclax has finally validated the potential of targeting apoptotic pathways in patients with cancer. Nevertheless, pharmacologic modulators of cell death have shown markedly varied responses in preclinical and clinical studies. Here, we review emerging concepts in the use of this class of therapies. Building on these observations, we propose that treatment-induced changes in apoptotic dependency, rather than pretreatment dependencies, will need to be recognized and targeted to realize the precise deployment of these new pharmacologic agents. Significance: Targeting antiapoptotic family members has proven efficacious and tolerable in some cancers, but responses are infrequent, particularly for patients with solid tumors. Biomarkers to aid patient selection have been lacking. Precision functional approaches that overcome adaptive resistance to these compounds could drive durable responses to chemotherapy, targeted therapy, and immunotherapies.

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Section: Reviewmentioning

confidence: 99%

Adapted to Survive: Targeting Cancer Cells with BH3 Mimetics

Montero

Haq

2022

Cancer Discovery

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“…A conserved BimBH3 peptide consisting of 14 residues was modified by inserting two cyclization constraints to generate bicyclic helical peptides, which were potent, cell-permeable, dual inhibitors of Bcl-2A1/Bfl-1 and Mcl-1 with high selectivity over other Bcl-2 proteins [ 121 ]. Another study reported the design of dual Mcl-1/Bfl-1 inhibitors based on benzoic acid scaffolds, where a compound 24 binds to both Mcl-1 and Bfl-1 with inhibitor constant Ki of 100 nmol/L and exhibits great selectivity over Bcl-2/Bcl-xl [ 122 ]. The natural compound marinopyrrole A has been shown to degrade Mcl-1 protein and thereby induce apoptosis in Mcl-1-dependent cancer cells [ 123 ].…”

Section: Therapeutic Targeting Of Mcl-1mentioning

confidence: 99%

Myeloid cell leukemia-1: a formidable barrier to anticancer therapeutics and the quest of targeting it

Sulkshane

Teni

2022

Exploration of Targeted Anti-Tumor Therapy

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The antiapoptotic B cell lymphoma-2 (Bcl-2) family members are apical regulators of the intrinsic pathway of apoptosis that orchestrate mitochondrial outer membrane permeabilization (MOMP) through interactions with their proapoptotic counterparts. Overexpression of antiapoptotic Bcl-2 family proteins has been linked to therapy resistance and poor prognosis in diverse cancers. Among the antiapoptotic Bcl-2 family members, predominant overexpression of the prosurvival myeloid cell leukemia-1 (Mcl-1) has been reported in a myriad of hematological malignancies and solid tumors, contributing to therapy resistance and poor outcomes, thus making it a potential druggable target. The unique structure of Mcl-1 and its complex regulatory mechanism makes it an adaptive prosurvival switch that ensures tumor cell survival despite therapeutic intervention. This review focusses on diverse mechanisms adopted by tumor cells to maintain sustained elevated levels of Mcl-1 and how high Mcl-1 levels contribute to resistance in conventional as well as targeted therapies. Moreover, recent developments in the Mcl-1-targeted therapeutics and the underlying challenges and considerations in designing novel Mcl-1 inhibitors are also discussed.

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“…An FP competition assay was used to evaluate the inhibitory activities of the compounds against Mcl-1, 75 Bcl-2, 68 and Bfl-1. 76 Different concentrations of compounds were prepared by serial dilution in assay buffer (Mcl-1: 20 mM Tris, 150 mM NaCl, 3 mM DTT, pH = 7.5; Bfl-1 and Bcl-2: 55 mM Hepes, 274 mM NaCl, 1.48 mM Na 2 HPO 4 , pH = 7.0). FITC-Bak-BH3 was chosen as a probe for Mcl-1 (10 nM final).…”

Section: ■ Experimental Sectionmentioning

confidence: 99%

Discovery of 3,5-Dimethyl-4-Sulfonyl-1H-Pyrrole-Based Myeloid Cell Leukemia 1 Inhibitors with High Affinity, Selectivity, and Oral Bioavailability

Zhu

et al. 2021

J. Med. Chem.

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Myeloid cell leukemia 1 (Mcl-1) protein is a key negative regulator of apoptosis, and developing Mcl-1 inhibitors has been an attractive strategy for cancer therapy. Herein, we describe the rational design, synthesis, and structure–activity relationship study of 3,5-dimethyl-4-sulfonyl-1H-pyrrole-based compounds as Mcl-1 inhibitors. Stepwise optimizations of hit compound 11 with primary Mcl-1 inhibition (52%@30 μM) led to the discovery of the most potent compound 40 with high affinity (K d = 0.23 nM) and superior selectivity over other Bcl-2 family proteins (>40,000 folds). Mechanistic studies revealed that 40 could activate the apoptosis signal pathway in an Mcl-1-dependent manner. 40 exhibited favorable physicochemical properties and pharmacokinetic profiles (F% = 41.3%). Furthermore, oral administration of 40 was well tolerated to effectively inhibit tumor growth (T/C = 37.3%) in MV4-11 xenograft models. Collectively, these findings implicate that compound 40 is a promising antitumor agent that deserves further preclinical evaluations.

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Discovery and Characterization of 2,5-Substituted Benzoic Acid Dual Inhibitors of the Anti-apoptotic Mcl-1 and Bfl-1 Proteins

Cited by 31 publications

References 72 publications

Adapted to Survive: Targeting Cancer Cells with BH3 Mimetics

Adapted to Survive: Targeting Cancer Cells with BH3 Mimetics

Myeloid cell leukemia-1: a formidable barrier to anticancer therapeutics and the quest of targeting it

Discovery of 3,5-Dimethyl-4-Sulfonyl-1H-Pyrrole-Based Myeloid Cell Leukemia 1 Inhibitors with High Affinity, Selectivity, and Oral Bioavailability

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