Tumor pyruvate kinase M2 modulators: a comprehensive account of activators and inhibitors as anticancer agents

Pyruvate kinase M2 (PKM2) catalyzes the conversion of phosphoenolpyruvate (PEP) to pyruvate. It plays a central role in the metabolic reprogramming of cancer cells and is expressed in most human tumors. It is essential in indiscriminate proliferation, survival, and tackling apoptosis in cancer cells...

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Published inMedChemComm Vol. 12; no. 7; pp. 1121 - 1141
Main Authors Rathod, Bhagyashri, Chak, Shivam, Patel, Sagarkumar, Shard, Amit
Format Journal Article
LanguageEnglish
Published England Royal Society of Chemistry 21.07.2021
RSC
Subjects
Anticancer properties
Antitumor agents
Apoptosis
Cancer
Cell proliferation
Chemistry
Drug development
Inhibitors
Kinases
Modulators
Pyruvate kinase
Pyruvic acid
Tumors
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Abstract Pyruvate kinase M2 (PKM2) catalyzes the conversion of phosphoenolpyruvate (PEP) to pyruvate. It plays a central role in the metabolic reprogramming of cancer cells and is expressed in most human tumors. It is essential in indiscriminate proliferation, survival, and tackling apoptosis in cancer cells. This positions PKM2 as a hot target in cancer therapy. Despite its well-known structure and several reported modulators targeting PKM2 as activators or inhibitors, a comprehensive review focusing on such modulators is lacking. Herein we summarize modulators of PKM2, the assays used to detect their potential, the preferable tense (T) and relaxed (R) states in which the enzyme resides, lacunae in existing modulators, and several strategies that may lead to effective anticancer drug development targeting PKM2. The review focuses on the tumor pyruvate kinase M2 (PKM2) modulators. Both activators and inhibitors developed against PKM2 are discussed.
AbstractList Pyruvate kinase M2 (PKM2) catalyzes the conversion of phosphoenolpyruvate (PEP) to pyruvate. It plays a central role in the metabolic reprogramming of cancer cells and is expressed in most human tumors. It is essential in indiscriminate proliferation, survival, and tackling apoptosis in cancer cells. This positions PKM2 as a hot target in cancer therapy. Despite its well-known structure and several reported modulators targeting PKM2 as activators or inhibitors, a comprehensive review focusing on such modulators is lacking. Herein we summarize modulators of PKM2, the assays used to detect their potential, the preferable tense (T) and relaxed (R) states in which the enzyme resides, lacunae in existing modulators, and several strategies that may lead to effective anticancer drug development targeting PKM2. The review focuses on the tumor pyruvate kinase M2 (PKM2) modulators. Both activators and inhibitors developed against PKM2 are discussed.
Pyruvate kinase M2 (PKM2) catalyzes the conversion of phosphoenolpyruvate (PEP) to pyruvate. It plays a central role in the metabolic reprogramming of cancer cells and is expressed in most human tumors. It is essential in indiscriminate proliferation, survival, and tackling apoptosis in cancer cells. This positions PKM2 as a hot target in cancer therapy. Despite its well-known structure and several reported modulators targeting PKM2 as activators or inhibitors, a comprehensive review focusing on such modulators is lacking. Herein we summarize modulators of PKM2, the assays used to detect their potential, the preferable tense (T) and relaxed (R) states in which the enzyme resides, lacunae in existing modulators, and several strategies that may lead to effective anticancer drug development targeting PKM2.
Author Patel, Sagarkumar
Chak, Shivam
Rathod, Bhagyashri
Shard, Amit
AuthorAffiliation National Institute of Pharmaceutical Education and Research Ahmedabad
Department of Medicinal Chemistry
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  surname: Patel
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BackLink https://www.ncbi.nlm.nih.gov/pubmed/34355179$$D View this record in MEDLINE/PubMed
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Notes Rathod Bhagyashri Ramesh received her B. Pharm degree from Swami Ramanand Teerth Marathwada University, Nanded, in 2017. She obtained her M.S in Medicinal Chemistry from NIPER-A under the guidance of Dr. Amit Shard.
Dr. Amit Shard received his M.Sc. degree in Pharmaceutical Chemistry and Ph. D from CSIR-Institute of Himalayan Bioresource Technology, Palampur. After completing his doctoral work, he joined as faculty at the National Institute of Pharmaceutical Education and Research-Ahmedabad in 2014. His research interests include the development of novel pyruvate kinase M2 modulators and computer-aided drug design.
Shivam Chak obtained his B. Pharm degree from Abdul Kalam Technical University, Uttar Pradesh, in 2017, and received his master's degree (M.S. Pharm) in Medicinal Chemistry from NIPER-Ahmedabad. He worked on the synthesis of the anticancer molecule containing trifluoroethanone substituted thiazoles under the guidance of Dr. Amit Shard.
Sagarkumar Patel completed his B. Pharm at Ganpat University, Gujarat, in 2014, and obtained his M. Tech (Pharm) degree from NIPER-Mohali in 2016. Now he is pursuing a Ph.D. in Medicinal Chemistry at the National Institute of Pharmaceutical Education and Research (NIPER)-Ahmedabad under the guidance of Dr. Amit Shard. His research area is the design and synthesis of pyruvate kinase M2 (PKM2) modulators.
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Snippet Pyruvate kinase M2 (PKM2) catalyzes the conversion of phosphoenolpyruvate (PEP) to pyruvate. It plays a central role in the metabolic reprogramming of cancer...
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SubjectTerms Anticancer properties
Antitumor agents
Apoptosis
Cancer
Cell proliferation
Chemistry
Drug development
Inhibitors
Kinases
Modulators
Pyruvate kinase
Pyruvic acid
Tumors
Title Tumor pyruvate kinase M2 modulators: a comprehensive account of activators and inhibitors as anticancer agents
URI https://www.ncbi.nlm.nih.gov/pubmed/34355179
https://www.proquest.com/docview/2553447955/abstract/
https://search.proquest.com/docview/2559428598
https://pubmed.ncbi.nlm.nih.gov/PMC8292966
Volume 12
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