Discovery and biological characterization of potent myeloid cell leukemia‐1 inhibitors

Lee, Min Ho; Bian, Zhiguo; Zhao, Bin; Hogdal, Leah J.; Sensintaffar, John; Goodwin, Craig M.; Belmar, Johannes; Shaw, Subrata; Tarr, James C.; Veerasamy, Nagarathanam; Matulis, Shannon M.; Koss, Brian; Fischer, Melissa A.; Arnold, Allison L.; Camper, DeMarco V.; Browning, Carrie F.; Rossanese, Olivia W.; Budhraja, Amit; Opferman, Joseph T.; Boise, Lawrence H.; Savona, Michael R.; Letaï, Anthony; Olejniczak, Edward T.; Fesik, Stephen W.

doi:10.1002/1873-3468.12497

Cited by 51 publications

(64 citation statements)

References 44 publications

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“…To further investigate the discordance between the mitochondrial and anti-apoptotic actions of MCL1, we used the BH3-mimetic small molecule MCL1 inhibitor VU0659158 (Lee et al, 2017). Since this drug specifically binds the BH3-binding groove and mimics the binding of pro-apoptotic BH3 family members, we hypothesized that VU0659158 would not affect MCL1 action in the mitochondrial matrix where multi-BH domain cell death effectors, such as BAX and BAK, are absent.…”

Section: Resultsmentioning

confidence: 99%

MYC and MCL1 Cooperatively Promote Chemotherapy-Resistant Breast Cancer Stem Cells via Regulation of Mitochondrial Oxidative Phosphorylation

et al. 2017

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Summary Most patients with advanced triple-negative breast cancer (TNBC) develop drug resistance. MYC and MCL1 are frequently co-amplified in drug-resistant TNBC after neoadjuvant chemotherapy. Herein, we demonstrate that MYC and MCL1 cooperate in the maintenance of chemotherapy-resistant cancer stem cells (CSCs) in TNBC. MYC and MCL1 increased mitochondrial oxidative phosphorylation (mtOXPHOS) and the generation of reactive oxygen species (ROS), processes involved in maintenance of CSCs. A mutant of MCL1 that cannot localize in mitochondria reduced mtOXPHOS, ROS levels and drug-resistant CSCs without affecting the anti-apoptotic function of MCL1. Increased levels of ROS, a by-product of activated mtOXPHOS, led to the accumulation of HIF-1α. Pharmacological inhibition of HIF-1α attenuated CSC enrichment and tumor initiation in vivo. These data suggest that 1) MYC and MCL1 confer resistance to chemotherapy by expanding CSCs via mtOXPHOS; and 2) targeting mitochondrial respiration and HIF-1α may reverse chemotherapy resistance in TNBC.

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Section: Resultsmentioning

confidence: 99%

MYC and MCL1 Cooperatively Promote Chemotherapy-Resistant Breast Cancer Stem Cells via Regulation of Mitochondrial Oxidative Phosphorylation

et al. 2017

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“…[140] Other compounds that inhibit MCL-1 at picomolar concentrations and cause MOMP and caspase activation in engineered cell lines, as well as inhibition of proliferation of primary MM and AML cells, have been discovered, laying the foundation for the development of clinical candidates. [141]…”

Section: Novel Compounds That Inhibit Bcl-xl or Mcl-1mentioning

confidence: 99%

Pathways and mechanisms of venetoclax resistance

Bose

Gandhi²,

Konopleva

2017

Leukemia & Lymphoma

230

195

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The approval of venetoclax, a “BH3-mimetic” antagonist of the BCL-2 anti-apoptotic protein, for chronic lymphocytic leukemia represents a major milestone in translational apoptosis research. Venetoclax has already received “breakthrough” designation for acute myeloid leukemia, and is being studied in many other tumor types. However, resistance to BCL-2 inhibitor monotherapy may rapidly ensue. Several studies have shown that the other two major anti-apoptotic BCL-2 family proteins, BCL-XL and MCL-1, are the main determinants of resistance to venetoclax. This opens up possibilities for rationally combining venetoclax with other targeted agents to circumvent resistance. Here, we summarize the most promising combinations, and highlight those already in clinical trials. There is also increasing recognition that different tumors display different degrees of addiction to individual BCL-2 family proteins, and of the need to refine current “BH3 profiling” techniques. Finally, the successful clinical development of potent and selective antagonists of BCL-XL and MCL-1 is eagerly awaited.

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“…These approaches led to larger P2-P4 binders such as A-1210477 by Abbvie [39] and compounds 4 and 5 by the Fesik lab [40], which exhibit subnanomolar affinity (Ki = 0.045 nM and Ki = 0.05 nM respectively) and selectivity >1,000-fold over BCL-2 and BCL-X L . These compounds induced single-agent mitochondrial apoptosis in MCL-1 dependent cell lines of hematologic cancers.…”

Section: Bh3 Mimetics Of Anti-apoptotic Bcl-2 Proteinsmentioning

confidence: 99%

Progress in targeting the BCL-2 family of proteins

Garner

López

Reyna

et al. 2017

Current Opinion in Chemical Biology

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The network of protein-protein interactions among the BCL-2 protein family plays a critical role in regulating cellular commitment to mitochondrial apoptosis. Anti-apoptotic BCL-2 proteins are considered promising targets for drug discovery and exciting clinical progress has stimulated intense investigations in the broader family. Here, we discuss recent developments in small molecules targeting anti-apoptotic proteins and alternative approaches to targeting BCL-2 family interactions. These studies advance our understanding of the role of BCL-2 family proteins in physiology and disease, providing unique tools for dissecting these functions. The BCL-2 family of proteins is a prime example of targeting protein-protein interactions and further chemical biology approaches will increase opportunities for novel targeted therapies in cancer, autoimmune and aging-associated diseases.

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Discovery and biological characterization of potent myeloid cell leukemia‐1 inhibitors

Cited by 51 publications

References 44 publications

MYC and MCL1 Cooperatively Promote Chemotherapy-Resistant Breast Cancer Stem Cells via Regulation of Mitochondrial Oxidative Phosphorylation

MYC and MCL1 Cooperatively Promote Chemotherapy-Resistant Breast Cancer Stem Cells via Regulation of Mitochondrial Oxidative Phosphorylation

Pathways and mechanisms of venetoclax resistance

Progress in targeting the BCL-2 family of proteins

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