Development of GLUT4-selective antagonists for multiple myeloma therapy

• 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
• Journal Title: European Journal of Medicinal Chemistry
• Volume: Volume 139
• Publisher: Elsevier | 2017-10-20, Pages 573-586
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1016/j.ejmech.2017.08.029
• Subjects: Health Sciences, Oncology; Health Sciences, Pharmacology
• Keywords: Science & Technology; Life Sciences & Biomedicine; Chemistry, Medicinal; Pharmacology & Pharmacy; GLUT4; Glucose; Multiple myeloma; GLUCOSE-TRANSPORTER GLUT4; HIV PROTEASE INHIBITORS; INSULIN-RESISTANCE; AEROBIC GLYCOLYSIS; CARDIAC MYOCYTES; DRUG-RESISTANCE; SKELETAL-MUSCLE; ADIPOSE-TISSUE; CANCER-CELLS; IN-VIVO

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.