Development of GLUT4-selective antagonists for multiple myeloma therapy

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 ret...

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Bibliographic Details
Published in:European journal of medicinal chemistry 2017-10, Vol.139, p.573-586
Main Authors: Wei, Changyong, Bajpai, Richa, Sharma, Horrick, Heitmeier, Monique, Jain, Atul D., Matulis, Shannon M., Nooka, Ajay K., Mishra, Rama K., Hruz, Paul W., Schiltz, Gary E., Shanmugam, Mala
Format: Article
Language:English
Subjects:
Animals
Antineoplastic Agents - chemical synthesis
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
Cell Death - drug effects
Cell Proliferation - drug effects
Cell Survival - drug effects
Dose-Response Relationship, Drug
Glucose
Glucose Transporter Type 4 - antagonists & inhibitors
Glucose Transporter Type 4 - metabolism
GLUT4
HEK293 Cells
Humans
Mice
Molecular Structure
Multiple myeloma
Multiple Myeloma - drug therapy
Multiple Myeloma - metabolism
Multiple Myeloma - pathology
Structure-Activity Relationship
Tumor Cells, Cultured
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Summary: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. [Display omitted] •A series of novel GLUT4 antagonists were designed and synthesized.•Lead compounds have high selectivity for GLUT4 versus other GLUT isoforms.•Compound 20 inhibits GLUT4-mediated glucose uptake and MM cell proliferation.•Treatment of patient samples with compound 20 causes sensitization to MM drugs.
ISSN:0223-5234
1768-3254
DOI:10.1016/j.ejmech.2017.08.029