Development of GLUT4-selective antagonists for multiple myeloma therapy

• Type of Material: Article
• Authors: Changyong Wei, Emory University; Richa Bajpai, Emory University; Horrick Sharma, Northwestern University; Monique Heitmeier, Washington University; Atul D. Jain, Northwestern University; Shannon M Matulis, Emory University; Ajay Nooka, Emory University; Rama K. Mishra, Northwestern University; Paul W. Hruz, Washington University; Gary E. Schiltz, Northwestern University; Mala Shanmugam, Emory University
• Language: English
• Date: 2017-10-20
• Publisher: Elsevier
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2017 Elsevier
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.ejmech.2017.08.029
• Title of Journal or Parent Work: European Journal of Medicinal Chemistry
• ISSN: 0223-5234
• Volume: 139
• Start Page: 573
• End Page: 586
• Grant/Funding Information: A part of this work was performed by the Northwestern University Medicinal and Synthetic Chemistry Core (ChemCore) at the Center for Molecular Innovation and Drug Discovery (CMIDD), which is funded by the Chicago Biomedical Consortium with support from The Searle Funds at The Chicago Community Trust, and Cancer Center Support Grant P30 CA060553 from the National Cancer Institute awarded to the Robert H. Lurie Comprehensive Cancer Center and by the American Cancer Society Research scholar grant (RSG-11-254-01-CSM) to Mala Shanmugam.
• Keywords: Science & Technology; AEROBIC GLYCOLYSIS; INSULIN-RESISTANCE; GLUT4; GLUCOSE-TRANSPORTER GLUT4; Life Sciences & Biomedicine; CARDIAC MYOCYTES; SKELETAL-MUSCLE; Glucose; IN-VIVO; HIV PROTEASE INHIBITORS; Pharmacology & Pharmacy; Chemistry, Medicinal; CANCER-CELLS; Multiple myeloma; DRUG-RESISTANCE; ADIPOSE-TISSUE
• Research Categories: Health Sciences, Pharmacology; Health Sciences, Oncology

Abstract

Masson SAS Cancer cells consume more glucose to fuel metabolic programs fundamental to sustaining their survival, growth and proliferation. Among the fourteen SLC2A family members, GLUTs 1 and 4 are high-affinity glucose transporters. GLUT4 (SLC2A4) is highly expressed in muscle and adipose tissue. Basally retained within the cell, GLUT4 traffics to the plasma membrane (PM) in response to insulin and exercise-stimulation. The plasma cell malignancy multiple myeloma (MM) exhibits increased constitutive expression of GLUT4 on the PM, co-opting use of GLUT4 for survival and proliferation. GLUT4 inhibition by knockdown or treatment with the FDA-approved HIV protease inhibitor ritonavir leads to cytostatic and/or cytotoxic and chemosensitizing effects in tumor cells both in vitro and in vivo. We recently reported our generation of GLUT4 homology models and virtual high-throughput screening (vHTS) to identify multiple series of novel GLUT4 antagonists. In this report, we describe our initial hit-to-lead optimization to synthesize new analogs with improved potency and selectivity for GLUT4, and the biological characterization of these compounds in a variety of assays. We show that our lead compound (compound 20) decreases glucose uptake and cell proliferation as well as inhibits the expression of pro-survival MCL-1 in MM similar to the effect observed via knockdown of GLUT4 expression. Compound 20 is also effective at chemosensitizing multiple myeloma cell lines and patient samples to venetoclax, dexamethasone and melphalan. In sum, we report development of selective GLUT4 inhibitors lacking inhibitory activity against GLUT1 and GLUT8. We show that selective pharmacological inhibition of GLUT4 is feasible and this may represent a novel strategy for the treatment and chemosensitization of multiple myeloma to standard therapeutics.