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Discovery of Macrocyclic Myeloid Cell Leukemia 1 (Mcl-1) Inhibitors that Demonstrate Potent Cellular Efficacy and In
James C Tarr1, Kyuok Jeon1, Nagarathanam Veerasamy1
1Department of Biochemistry, Vanderbilt University School of Medicine, 2215 Garland Avenue, 607 Light Hall, Nashville, Tennessee 37232-0146, United States.
Abstract:
The B cell lymphoma 2 (Bcl-2) family of proteins are key regulators of intrinsic apoptosis. The antiapoptotic protein myeloid cell leukemia 1 (Mcl-1), which is associated with high tumor grade, poor survival, and resistance to treatment, has emerged as a promising candidate for treating hematological and solid cancers. Herein, we report the structure-guided design of small molecule macrocyclic Mcl-1 inhibitors based on the (R)-methyl-dihydropyrazinoindolone scaffold our group has previously disclosed. The macrocyclic inhibitors bind Mcl-1 with subnanomolar affinity and offer improved potency in cell culture growth inhibition assays. Inhibitor 13 achieved tumor regression in a lung cancer-derived tumor xenograft model in mice as a monotherapy. The improved potency of the macrocyclic series allowed replacement of heretofore conserved indole carboxylic acid moiety, resulting in neutral inhibitors. Amide inhibitor 25 displayed a >10-fold increase in oral bioavailability as compared to acid-containing macrocyclic or acyclic inhibitors.
Insights
Researchers designed novel macrocyclic inhibitors targeting myeloid cell leukemia 1 (Mcl-1), a protein linked to cancer progression. These potent Mcl-1 inhibitors show promise in preclinical models and improved oral bioavailability for cancer therapy.
Area of Science:
- Medicinal Chemistry
- Molecular Biology
- Cancer Research
Background:
- The B cell lymphoma 2 (Bcl-2) protein family regulates apoptosis.
- Myeloid cell leukemia 1 (Mcl-1) is an antiapoptotic protein implicated in various cancers, associated with poor prognosis and treatment resistance.
Purpose of the Study:
- To design and synthesize novel small molecule macrocyclic inhibitors targeting Mcl-1.
- To evaluate the in vitro and in vivo efficacy of these Mcl-1 inhibitors.
Main Methods:
- Structure-guided design of macrocyclic compounds based on a pyrazinoindolone scaffold.
- Biochemical assays to determine binding affinity to Mcl-1.
- Cell culture assays for growth inhibition.
- In vivo studies using a lung cancer xenograft model in mice.
Main Results:
- Macrocyclic inhibitors demonstrated subnanomolar affinity for Mcl-1.
- Compounds showed enhanced potency in cell growth inhibition assays.
- Inhibitor 13 achieved tumor regression as a monotherapy in a lung cancer xenograft model.
- A neutral amide inhibitor (25) exhibited >10-fold increased oral bioavailability compared to acidic counterparts.
Conclusions:
- The developed macrocyclic Mcl-1 inhibitors represent a promising therapeutic strategy for Mcl-1-dependent cancers.
- Optimization led to compounds with improved potency and pharmacokinetic properties, including enhanced oral bioavailability.
