It has long been known that tumor cells rewire their metabolism to ensure proliferation and survival. Emerging genetic evidence has demonstrated the importance of many metabolic enzymes in supporting cancer metabolism, in particular the oxidoreductases, which catalyze electron transfer reactions and are the largest family of metabolic enzymes. Yet, the metabolites that bind and regulate this class of metabolic enzymes are not fully characterized, and there are no small molecule inhibitors for the majority of the oxidoreductases. Because there is an oxidoreductase in nearly every metabolic pathway, small molecule inhibitors of the oxidoreductases would be useful for studying the role of metabolism in a variety of tumor models. As a starting point for targeting the oxidoreductases, we have developed inhibitors of 3-phosphoglycerate dehydrogenase (PHGDH), the first enzyme in the serine biosynthesis pathway, and shown that these compounds are selectively toxic towards PHGDH-dependent, estrogen receptor-negative cell lines, even in the presence of exogenous serine. These compounds prevent the incorporation of both endogenously produced and exogenous serine, via one-carbon units, into nucleotides needed for proliferation, implying that serine synthesis not only controls the production but also the fate of serine-derived one-carbon units needed for biosynthesis. While this may account for the toxicity of PHGDH knockdown or inhibition in the presence of abundant exogenous serine, the mechanism by which serine synthesis pathway activity ensures the availability of one-carbon units for biosynthesis is unknown. In this proposal, building on my previous work, we will test the hypothesis that a serine synthesis pathway metabolite coordinates the fate of one-carbon units (Aim 1), and define the spectrum of endogenous metabolites that bind and regulate the oxidoreductases and other metabolic enzymes (Aim 2). To extend extend the techniques used to target PHGDH to other oxidoreductases, we will build tools to enable the systematic discovery of oxidoreductase inhibitors (Aim 3). Compounds emerging from these efforts will advance our mechanistic understanding of metabolism in a variety of cellular contexts, and might serve as proof of concept for the development of novel antimetabolites.
Tumor cells rewire their metabolism to produce a steady supply of molecular building blocks needed for their survival, growth, and proliferation. Antimetabolite chemotherapeutics, which inhibit the altered metabolism of tumors, have a long track record of improving the survival of patients with cancer. Yet, only one new class of antimetabolites has entered clinical trials in the past decade. I will develop techniques for systematically identify novel metabolic enzyme inhibitors to advance our understanding of metabolism in the laboratory, and to serve as proof of concept for novel antimetabolites that might be useful in the treatment of cancer.
|Rohde, Jason M; Brimacombe, Kyle R; Liu, Li et al. (2018) Discovery and optimization of piperazine-1-thiourea-based human phosphoglycerate dehydrogenase inhibitors. Bioorg Med Chem 26:1727-1739|