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Therapeutic targeting of the mitochondrial one-carbon pathway: perspectives, pitfalls, and potential

Zhao, Li Na ; Björklund, Mikael ; Caldez, Matias J ; Zheng, Jie and Kaldis, Philipp LU orcid (2021) In Oncogene
Abstract

Most of the drugs currently prescribed for cancer treatment are riddled with substantial side effects. In order to develop more effective and specific strategies to treat cancer, it is of importance to understand the biology of drug targets, particularly the newly emerging ones. A comprehensive evaluation of these targets will benefit drug development with increased likelihood for success in clinical trials. The folate-mediated one-carbon (1C) metabolism pathway has drawn renewed attention as it is often hyperactivated in cancer and inhibition of this pathway displays promise in developing anticancer treatment with fewer side effects. Here, we systematically review individual enzymes in the 1C pathway and their compartmentalization to... (More)

Most of the drugs currently prescribed for cancer treatment are riddled with substantial side effects. In order to develop more effective and specific strategies to treat cancer, it is of importance to understand the biology of drug targets, particularly the newly emerging ones. A comprehensive evaluation of these targets will benefit drug development with increased likelihood for success in clinical trials. The folate-mediated one-carbon (1C) metabolism pathway has drawn renewed attention as it is often hyperactivated in cancer and inhibition of this pathway displays promise in developing anticancer treatment with fewer side effects. Here, we systematically review individual enzymes in the 1C pathway and their compartmentalization to mitochondria and cytosol. Based on these insight, we conclude that (1) except the known 1C targets (DHFR, GART, and TYMS), MTHFD2 emerges as good drug target, especially for treating hematopoietic cancers such as CLL, AML, and T-cell lymphoma; (2) SHMT2 and MTHFD1L are potential drug targets; and (3) MTHFD2L and ALDH1L2 should not be considered as drug targets. We highlight MTHFD2 as an excellent therapeutic target and SHMT2 as a complementary target based on structural/biochemical considerations and up-to-date inhibitor development, which underscores the perspectives of their therapeutic potential.

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author
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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Oncogene
publisher
Nature Publishing Group
external identifiers
  • scopus:85103524719
  • pmid:33664451
ISSN
1476-5594
DOI
10.1038/s41388-021-01695-8
language
English
LU publication?
yes
id
a8622f40-b190-4ca9-b35e-66b0db852cc7
date added to LUP
2021-03-08 09:37:04
date last changed
2024-03-21 02:59:56
@article{a8622f40-b190-4ca9-b35e-66b0db852cc7,
  abstract     = {{<p>Most of the drugs currently prescribed for cancer treatment are riddled with substantial side effects. In order to develop more effective and specific strategies to treat cancer, it is of importance to understand the biology of drug targets, particularly the newly emerging ones. A comprehensive evaluation of these targets will benefit drug development with increased likelihood for success in clinical trials. The folate-mediated one-carbon (1C) metabolism pathway has drawn renewed attention as it is often hyperactivated in cancer and inhibition of this pathway displays promise in developing anticancer treatment with fewer side effects. Here, we systematically review individual enzymes in the 1C pathway and their compartmentalization to mitochondria and cytosol. Based on these insight, we conclude that (1) except the known 1C targets (DHFR, GART, and TYMS), MTHFD2 emerges as good drug target, especially for treating hematopoietic cancers such as CLL, AML, and T-cell lymphoma; (2) SHMT2 and MTHFD1L are potential drug targets; and (3) MTHFD2L and ALDH1L2 should not be considered as drug targets. We highlight MTHFD2 as an excellent therapeutic target and SHMT2 as a complementary target based on structural/biochemical considerations and up-to-date inhibitor development, which underscores the perspectives of their therapeutic potential.</p>}},
  author       = {{Zhao, Li Na and Björklund, Mikael and Caldez, Matias J and Zheng, Jie and Kaldis, Philipp}},
  issn         = {{1476-5594}},
  language     = {{eng}},
  month        = {{03}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Oncogene}},
  title        = {{Therapeutic targeting of the mitochondrial one-carbon pathway: perspectives, pitfalls, and potential}},
  url          = {{http://dx.doi.org/10.1038/s41388-021-01695-8}},
  doi          = {{10.1038/s41388-021-01695-8}},
  year         = {{2021}},
}