Targeting metabolic vulnerabilities of cancer: Small molecule inhibitors in clinic

Abstract

Background: Altered cell metabolism is an established hallmark of cancer. Advancement in our understanding of dysregulated cellular metabolism has aided drastically in identifying metabolic vulnerabilities that can be exploited therapeutically. Indeed, this knowledge has led to the development of a multitude of agents targeting various aspects of tumor metabolism. Recent findings:The intent of this review is to provide insight into small molecule inhibitors that target tumor metabolism and that are currently being explored in active clinical trials as either preventive, stand-alone, or adjuvant therapies for various malignancies. For each inhibitor, we outline the mechanism (s) of action, preclinical/clinical findings, and limitations. Sections are divided into three aspects based on the primary target of the small molecule inhibitor (s): those that impact (1) cancer cells directly, (2) immune cells present in the tumor microenvironment, or (3) both cancer cells and immune cells. We highlight small molecule targeting of metabolic pathways including de novo fatty acid synthesis, NAD+ biosynthesis, 2-hydroxyglutarate biosynthesis, polyamine metabolism, the kynurenine pathway, as well as glutamine and arginine metabolism.Conclusions: Use of small molecule inhibitors aimed at exploiting tumor metabolic vulnerabilities continues to be an active area of research. Identifying metabolic dependencies specific to cancer cells and/or constituents of the tumor microenvironment is a viable area of therapeutic intervention that holds considerable clinical potential. pump inhibitors; QPRT, quinolinate phosphoribosyltransferase; R/R, relapsed/refractory; SAT1, spermidine/spermine N1-acetyltransferase; SCS, succinate-CoA ligase; SDH, succinate dehydrogenase; SLC1A5, soluble carrier family 1 member 5; SMS, spermine synthase; TCA, tricarboxylic acid cycle; TDO, tryptophan 2,3-dioxygenase; TPI, triosephosphate isomerase; α-KG, alpha-ketoglutarate Satyendra C. Tripathi and Johannes F. Fahrmann contributed equally to the manuscript.

Metabolic rewiring in the promotion of cancer metastasis: mechanisms and therapeutic implications

“… N.A. [ 128 , 151 ] Cholesterol metabolism inhibitors: N.A. Simvastatin, Pravastatin HMGCR Statins inhibit cholesterol biosynthesis and protein prenylyation.…”

“…Omeprazole, a proton pump inhibitor, was shown to inhibit the thioesterase domain of FASN and prevent release of free palmitate from acyl carrier protein. The blockade of FASN by Omeprazole reduced palmitate and dose-dependently inhibited breast cancer cell invasion and metastasis [ 128 ].…”

Amino Acid Oncometabolism and Immunomodulation of the Tumor Microenvironment in Lung Cancer

“…Many cancers, in particular, lymphomas, melanoma, mesothelioma, and hepatocellular, renal cell, and prostate carcinomas that are otherwise chemoresistant and with poor clinical outcome, exhibit decreased expression of arginine metabolizing enzymes including argininosuccinate synthetase (ASS1) and/or ornithine transcarbamylase (OTC) and are thus auxotrophic for arginine (74). Deprivation of circulating arginine via enzymes such as arginase, arginine deiminase (ADI), and arginine decarboxylase (ADC) exploits a significant metabolic vulnerability of cancer cells in these tumor types, and such enzyme-mediated arginine depletion is currently under clinical investigation along multiple fronts to advance this potential class of anticancer therapeutics (75)(76)(77). While positive results have been reported in this regard, the role of arginine in tumors in general is multidimensional.…”

Inhibition of Cancer Metabolism: a Patent Landscape

“…However, the TCA cycle, glycolysis and anaplerosis are just some of the many metabolic processes in cells. Other pathways, such as the pentose-phosphate shunt, nucleotide biosynthesis, fatty acid synthesis and polyamine synthesis are all critically implicated in cellular metabolism, and many of these have also been the target of significant drug discovery efforts [24,118]. Moreover, we have limited ourselves primarily to a consideration of small molecules that directly act on the targets of interest.…”