Challenges and Opportunities in the Development of Serine Synthetic Pathway Inhibitors for Cancer Therapy

Abstract

Recent advances in the understanding of the relationship between cancer and metabolism have highlighted the relevance of the serine synthetic pathway (SSP), which consists of three successive enzymatic reactions. Enzymes of the SSP, such as phosphoglycerate dehydrogenase (PHGDH) and phosphoserine aminotransferase 1 (PSAT-1), were recently highlighted because they are amplified in a significant subset of human tumors, and their suppression by RNAi caused a decrease in cancer cell survival and growth. Currently, the discovery of drugs that inhibit these enzymes is still in its infancy, and the identification of suitable inhibitors could serve to understand the emerging biology of these metabolic enzymes. In this review, we present the SSP as a significant and novel emerging area for medicinal chemistry and we provide an overview of one of the key enzymes of the pathway, PHGDH.

Differential Proteomic Analysis between Small Cell Lung Carcinoma (SCLC) and Pulmonary Carcinoid Tumors Reveals Molecular Signatures for Malignancy in Lung Cancer

“…The oncogenic role and prognostic value of PHGDH, which catalyzes the first rate‐limiting step in serine biosynthesis, has been investigated in multiple cancer types, including breast cancer, melanoma, cervical cancer, and colon cancer, as well as lung cancer . An analysis of a large panel of NSCLC cell lines also revealed that NRF2 (not detected in this study) controls PHGDH expression, which confers poor prognosis in NSCLC patients . We identified a significantly high expression at the protein levels of PHGDH and also SHMT2 (FC, 5.68; p < 0.0001), by which serine can be converted into glycine, in tumor cells of SCLC patients.…”

“…Tumors have exceptionally high energetic and anabolic requirements due to rapid cell growth and proliferation, and the serine biosynthetic pathway was recently identified as an important source of metabolic intermediates for these processes. The oncogenic role and prognostic value of PHGDH, which catalyzes the first rate‐limiting step in serine biosynthesis, has been investigated in multiple cancer types, including breast cancer, melanoma, cervical cancer, and colon cancer, as well as lung cancer . An analysis of a large panel of NSCLC cell lines also revealed that NRF2 (not detected in this study) controls PHGDH expression, which confers poor prognosis in NSCLC patients .…”

“…We identified a significantly high expression at the protein levels of PHGDH and also SHMT2 (FC, 5.68; p < 0.0001), by which serine can be converted into glycine, in tumor cells of SCLC patients. Currently, the development of serine and glycine biosynthetic pathway inhibitors for cancer therapy is in progress …”

The Role of D-3-Phosphoglycerate Dehydrogenase in Cancer

“…In human PHGDH, the active site consists of the substrate-binding domain and nucleotide domain. It is lined by several loop regions of the first monomers Arg54-Val59, Ala76-Val83, Asn97-Gly101, Gly152-Leu153, Asp175-Ile178, His206-Leu216, Cys234-Val240, Asp260-Asp269, and Cys281-Ser287 and one loop of the second monomer Trp133-Lys136 [29].…”

Discovery and optimization of piperazine-1-thiourea-based human phosphoglycerate dehydrogenase inhibitors

“…[1][2] Given PHGDH's potential as a drug target in certain cancers, a number of PHGDH inhibitors have been reported. [3][4][5][6][7][8][9][10][11] AstraZeneca used a fragment-based lead discovery approach followed by medicinal chemistry optimization to develop an indole derivative ( Figure 1) with submicromolar K D . [4][5] Cantley and colleagues used a biochemical high-throughput screen to identify a PHGDH inhibitor (CBR-5884, Figure 1) with an IC 50 of ~33 μM.…”