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Title: | Early Drug Discovery and Development of Novel Cancer Therapeutics Targeting DNA Polymerase Eta (POLH) | Authors: | WILSON, David Duncton, Matthew A. J. Chang, Caleb Lee Luo, Christie Georgiadis, Taxiarchis M. Pellicena, Patricia Deacon, Ashley M. Gao, Yang Das, Debanu |
Issue Date: | 2021 | Publisher: | FRONTIERS MEDIA SA | Source: | Frontiers in Oncology, 11 (Art N° 778925) | Abstract: | Polymerase eta (or Pol eta 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. | Notes: | Das, D (corresponding author), XPose Therapeutics Inc, San Carlos, CA USA. info@xposetx.com |
Keywords: | fragment-based drug discovery (FBDD);structure-based drug discovery (SBDD);X-ray crystallography;cancer therapeutics;DNA damage response (DDR);polymerases;Pol eta;POLH | Document URI: | http://hdl.handle.net/1942/36543 | ISSN: | 2234-943X | e-ISSN: | 2234-943X | DOI: | 10.3389/fonc.2021.778925 | ISI #: | WOS:000738779600001 | Rights: | 2021 Wilson, Duncton, Chang, Lee Luo, Georgiadis, Pellicena, Deacon, Gao and Das. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. | Category: | A1 | Type: | Journal Contribution | Validations: | ecoom 2023 |
Appears in Collections: | Research publications |
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Early Drug Discovery and Development of Novel Cancer Therapeutics Targeting DNA Polymerase Eta (POLH).pdf | Published version | 21.94 MB | Adobe PDF | View/Open |
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