Discovery of PHGDH inhibitors by virtual screening and preliminary structure–activity relationship study

Zhang, Fu-Mao; Liang, Yuan; Shi, Xinwei; Feng, Kairui; Lan, Xiaojing; Huang, Cheng; Lin, Guo‐Qiang; Tian, Ping; Huang, Min; Tang, Shuai; Gao, Dingding

doi:10.1016/j.bioorg.2022.105705

Cited by 9 publications

(5 citation statements)

References 38 publications

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“…tuberculosis (PDB ID: 1YGY) as the template. , Then, the catalytic subunit was replaced with the crystal structure (PDB ID: 2G76). D8 was docked into the NAD + -binding site based on the previously reported procedure . The initial binding mode of D8 was selected from the docking results, highlighting the binding site in the newest structure (PDB ID: 7VA1) and the orientation of NAD + in 2G76.…”

Section: Methodsmentioning

confidence: 99%

“…Several PHGDH inhibitors have been reported and divided into two categories based on their binding sites: orthosteric and allosteric. As shown in Figure , the representative orthosteric inhibitors contain indole or carboxyl functional groups located at the binding pocket of cofactor NAD + (compounds 1 – 5 ). − These orthosteric inhibitors depict excellent enzymatic inhibitory activity, but poor antiproliferative activity against tumor cells, without any previously reported in vivo anti-tumor studies. The representative allosteric inhibitors include CBR-5884 ( 6 ), NCT-503 ( 7 ), 8 , PKUMDL-WQ-2201 ( 9 ), and Withangulatin A ( 10 ). − Although the reported allosteric inhibitors show potent enzymatic and cell proliferative inhibitory activities, most of them have undefined binding sites except withangulatin A.…”

Section: Introductionmentioning

confidence: 99%

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Discovery of Novel Drug-like PHGDH Inhibitors to Disrupt Serine Biosynthesis for Cancer Therapy

et al. 2023

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Being the rate-limiting enzyme within the serine biosynthesis pathway, phosphoglycerate dehydrogenase (PHGDH) is abnormally overexpressed in numerous malignant tumor cells and is a promising target for cancer treatment. Here, we report a series of novel PHGDH inhibitors using a focused compound screening and structural optimization approach. The lead compound D8 displayed good enzymatic inhibitory activity (IC50 = 2.8 ± 0.1 μM), high binding affinity (K d = 2.33 μM), and sensitivity to the cell lines with the PHGDH gene amplification or overexpression. Furthermore, D8 was proven to restrict the de novo serine synthesis from glucose within MDA-MB-468 cells. X-ray crystallographic analysis, molecular dynamics simulations, and mutagenesis experiments on PHGDH revealed the binding site at D175 inside the NAD+-binding pocket. Finally, D8 exhibited excellent in vivo pharmacokinetic properties (F = 82.0%) and exerted evident antitumor efficacy in the PC9 xenograft mouse model.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Discovery of Novel Drug-like PHGDH Inhibitors to Disrupt Serine Biosynthesis for Cancer Therapy

et al. 2023

Self Cite

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“…We performed the literature searching and collected 31 compounds with corresponding IC 50 values ranging from 0.002 µM to 68 µM (Fig S1 , S2) [2,3,5,10]. The "Generate Training and Test Data" protocol offered a random way to split a data set into 22 training set compounds and 9 test set compounds by setting the training set percentage as 80.…”

Section: D-qsar Pharmacophore Model Generationmentioning

confidence: 99%

“…PHGDH is abnormally expressed in various malignant tumor cells including: hepatocellular carcinoma, breast cancer, melanoma, lung cancer, glioma, colon carcinoma, ewing sarcoma, pancreatic cancer, leukemia, thyroid carcinoma, multiple myeloma, lymphoma and gastric and bladder cancer [2]. PHGDH dysregulation is a prevalent feature in a signi cant portion of malignancies with respect to their generation, proliferation, differentiation, and metastatic progress, which suggests that targeting PHGDH is a very promising direction in drug discovery of anti-cancer [3][4][5].…”

Section: Introductionmentioning

confidence: 99%

Identification of novel PHGDH inhibitors based on computational investigation: an all-in-one combination strategy to develop potential anti-cancer candidates

Xu,

Yang,

Yang

et al. 2024

Preprint

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PHGDH has been identified as a promising drug target for the therapy/management of various cancers. 3D-QSAR pharmacophore model-based virtual screening, ADME/T prediction, molecular docking, lead optimization and molecular dynamics simulation were utilized to identify novel potential PHGDH inhibitors. A ligand-based 3D-QSAR pharmacophore model was developed using HypoGen algorithm methodology of Discovery Studio. The selected Hypo_2 pharmacophore model was further validated by test set validation, cost analysis, Fischer randomization validation and was then used as a 3D query to screen compound libraries with various chemical scaffolds. Estimated activity, drug-likeness, molecular docking, growing scaffold and molecular dynamics simulation were applied in combination in order to further narrow the number of virtual hits. Finally, an all-in-one combination was employed successfully to design and develop two potential anti-cancer candidates.

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“…Novel PHGDH inhibitors have been screened out recently, which could play a huge role in future BC treatment. The newest compounds include CBR-5884 [ 116 ], C25 [ 117 ], and NCT-502 and NCT-503 [ 118 ]. All compounds have their pros and cons but it is concluded that most of them still show limited efficacy and selectivity [ 119 ].…”

Section: Mrs Under Amino Acid Metabolismmentioning

confidence: 99%

Potential Therapies Targeting the Metabolic Reprogramming of Diabetes-Associated Breast Cancer

Shum

Vadgama

et al. 2023

JPM

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In recent years, diabetes-associated breast cancer has become a significant clinical challenge. Diabetes is not only a risk factor for breast cancer but also worsens its prognosis. Patients with diabetes usually show hyperglycemia and hyperinsulinemia, which are accompanied by different glucose, protein, and lipid metabolism disorders. Metabolic abnormalities observed in diabetes can induce the occurrence and development of breast cancer. The changes in substrate availability and hormone environment not only create a favorable metabolic environment for tumorigenesis but also induce metabolic reprogramming events required for breast cancer cell transformation. Metabolic reprogramming is the basis for the development, swift proliferation, and survival of cancer cells. Metabolism must also be reprogrammed to support the energy requirements of the biosynthetic processes in cancer cells. In addition, metabolic reprogramming is essential to enable cancer cells to overcome apoptosis signals and promote invasion and metastasis. This review aims to describe the major metabolic changes in diabetes and outline how cancer cells can use cellular metabolic changes to drive abnormal growth and proliferation. We will specifically examine the mechanism of metabolic reprogramming by which diabetes may promote the development of breast cancer, focusing on the role of glucose metabolism, amino acid metabolism, and lipid metabolism in this process and potential therapeutic targets. Although diabetes-associated breast cancer has always been a common health problem, research focused on finding treatments suitable for the specific needs of patients with concurrent conditions is still limited. Most studies are still currently in the pre-clinical stage and mainly focus on reprogramming the glucose metabolism. More research targeting the amino acid and lipid metabolism is needed.

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Discovery of PHGDH inhibitors by virtual screening and preliminary structure–activity relationship study

Cited by 9 publications

References 38 publications

Discovery of Novel Drug-like PHGDH Inhibitors to Disrupt Serine Biosynthesis for Cancer Therapy

Discovery of Novel Drug-like PHGDH Inhibitors to Disrupt Serine Biosynthesis for Cancer Therapy

Identification of novel PHGDH inhibitors based on computational investigation: an all-in-one combination strategy to develop potential anti-cancer candidates

Potential Therapies Targeting the Metabolic Reprogramming of Diabetes-Associated Breast Cancer

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