Early Drug Discovery and Development of Novel Cancer Therapeutics Targeting DNA Polymerase Eta (POLH)

Polymerase eta (or Pol η or POLH) is a specialized DNA polymerase that is able to bypass certain blocking lesions, such as those generated by ultraviolet radiation (UVR) or cisplatin, and is deployed to replication foci for translesion synthesis as part of the DNA damage response (DDR). Inherited de...

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Autores principales:	David M. Wilson, Matthew A. J. Duncton, Caleb Chang, Christie Lee Luo, Taxiarchis M. Georgiadis, Patricia Pellicena, Ashley M. Deacon, Yang Gao, Debanu Das
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	fragment-based drug discovery (FBDD) structure-based drug discovery (SBDD) X-ray crystallography cancer therapeutics DNA damage response (DDR) polymerases Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/40bb23ee3ada4b41a46d7f5aa6c07ebc
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spelling	oai:doaj.org-article:40bb23ee3ada4b41a46d7f5aa6c07ebc2021-11-30T19:46:39ZEarly Drug Discovery and Development of Novel Cancer Therapeutics Targeting DNA Polymerase Eta (POLH)2234-943X10.3389/fonc.2021.778925https://doaj.org/article/40bb23ee3ada4b41a46d7f5aa6c07ebc2021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fonc.2021.778925/fullhttps://doaj.org/toc/2234-943XPolymerase eta (or Pol η or POLH) is a specialized DNA polymerase that is able to bypass certain blocking lesions, such as those generated by ultraviolet radiation (UVR) or cisplatin, and is deployed to replication foci for translesion synthesis as part of the DNA damage response (DDR). Inherited defects in the gene encoding POLH (a.k.a., XPV) are associated with the rare, sun-sensitive, cancer-prone disorder, xeroderma pigmentosum, owing to the enzyme’s ability to accurately bypass UVR-induced thymine dimers. In standard-of-care cancer therapies involving platinum-based clinical agents, e.g., cisplatin or oxaliplatin, POLH can bypass platinum-DNA adducts, negating benefits of the treatment and enabling drug resistance. POLH inhibition can sensitize cells to platinum-based chemotherapies, and the polymerase has also been implicated in resistance to nucleoside analogs, such as gemcitabine. POLH overexpression has been linked to the development of chemoresistance in several cancers, including lung, ovarian, and bladder. Co-inhibition of POLH and the ATR serine/threonine kinase, another DDR protein, causes synthetic lethality in a range of cancers, reinforcing that POLH is an emerging target for the development of novel oncology therapeutics. Using a fragment-based drug discovery approach in combination with an optimized crystallization screen, we have solved the first X-ray crystal structures of small novel drug-like compounds, i.e., fragments, bound to POLH, as starting points for the design of POLH inhibitors. The intrinsic molecular resolution afforded by the method can be quickly exploited in fragment growth and elaboration as well as analog scoping and scaffold hopping using medicinal and computational chemistry to advance hits to lead. An initial small round of medicinal chemistry has resulted in inhibitors with a range of functional activity in an in vitro biochemical assay, leading to the rapid identification of an inhibitor to advance to subsequent rounds of chemistry to generate a lead compound. Importantly, our chemical matter is different from the traditional nucleoside analog-based approaches for targeting DNA polymerases.David M. WilsonDavid M. WilsonMatthew A. J. DunctonCaleb ChangChristie Lee LuoTaxiarchis M. GeorgiadisPatricia PellicenaAshley M. DeaconYang GaoDebanu DasFrontiers Media S.A.articlefragment-based drug discovery (FBDD)structure-based drug discovery (SBDD)X-ray crystallographycancer therapeuticsDNA damage response (DDR)polymerasesNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENFrontiers in Oncology, Vol 11 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	fragment-based drug discovery (FBDD) structure-based drug discovery (SBDD) X-ray crystallography cancer therapeutics DNA damage response (DDR) polymerases Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	fragment-based drug discovery (FBDD) structure-based drug discovery (SBDD) X-ray crystallography cancer therapeutics DNA damage response (DDR) polymerases Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 David M. Wilson David M. Wilson Matthew A. J. Duncton Caleb Chang Christie Lee Luo Taxiarchis M. Georgiadis Patricia Pellicena Ashley M. Deacon Yang Gao Debanu Das Early Drug Discovery and Development of Novel Cancer Therapeutics Targeting DNA Polymerase Eta (POLH)
description	Polymerase eta (or Pol η or POLH) is a specialized DNA polymerase that is able to bypass certain blocking lesions, such as those generated by ultraviolet radiation (UVR) or cisplatin, and is deployed to replication foci for translesion synthesis as part of the DNA damage response (DDR). Inherited defects in the gene encoding POLH (a.k.a., XPV) are associated with the rare, sun-sensitive, cancer-prone disorder, xeroderma pigmentosum, owing to the enzyme’s ability to accurately bypass UVR-induced thymine dimers. In standard-of-care cancer therapies involving platinum-based clinical agents, e.g., cisplatin or oxaliplatin, POLH can bypass platinum-DNA adducts, negating benefits of the treatment and enabling drug resistance. POLH inhibition can sensitize cells to platinum-based chemotherapies, and the polymerase has also been implicated in resistance to nucleoside analogs, such as gemcitabine. POLH overexpression has been linked to the development of chemoresistance in several cancers, including lung, ovarian, and bladder. Co-inhibition of POLH and the ATR serine/threonine kinase, another DDR protein, causes synthetic lethality in a range of cancers, reinforcing that POLH is an emerging target for the development of novel oncology therapeutics. Using a fragment-based drug discovery approach in combination with an optimized crystallization screen, we have solved the first X-ray crystal structures of small novel drug-like compounds, i.e., fragments, bound to POLH, as starting points for the design of POLH inhibitors. The intrinsic molecular resolution afforded by the method can be quickly exploited in fragment growth and elaboration as well as analog scoping and scaffold hopping using medicinal and computational chemistry to advance hits to lead. An initial small round of medicinal chemistry has resulted in inhibitors with a range of functional activity in an in vitro biochemical assay, leading to the rapid identification of an inhibitor to advance to subsequent rounds of chemistry to generate a lead compound. Importantly, our chemical matter is different from the traditional nucleoside analog-based approaches for targeting DNA polymerases.
format	article
author	David M. Wilson David M. Wilson Matthew A. J. Duncton Caleb Chang Christie Lee Luo Taxiarchis M. Georgiadis Patricia Pellicena Ashley M. Deacon Yang Gao Debanu Das
author_facet	David M. Wilson David M. Wilson Matthew A. J. Duncton Caleb Chang Christie Lee Luo Taxiarchis M. Georgiadis Patricia Pellicena Ashley M. Deacon Yang Gao Debanu Das
author_sort	David M. Wilson
title	Early Drug Discovery and Development of Novel Cancer Therapeutics Targeting DNA Polymerase Eta (POLH)
title_short	Early Drug Discovery and Development of Novel Cancer Therapeutics Targeting DNA Polymerase Eta (POLH)
title_full	Early Drug Discovery and Development of Novel Cancer Therapeutics Targeting DNA Polymerase Eta (POLH)
title_fullStr	Early Drug Discovery and Development of Novel Cancer Therapeutics Targeting DNA Polymerase Eta (POLH)
title_full_unstemmed	Early Drug Discovery and Development of Novel Cancer Therapeutics Targeting DNA Polymerase Eta (POLH)
title_sort	early drug discovery and development of novel cancer therapeutics targeting dna polymerase eta (polh)
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/40bb23ee3ada4b41a46d7f5aa6c07ebc
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Early Drug Discovery and Development of Novel Cancer Therapeutics Targeting DNA Polymerase Eta (POLH)

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