In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 7_Supplement ( 2023-04-04), p. 1657-1657
Abstract:
Thymidylate synthase (TYMS/TS) is overexpressed in many cancer types and is commonly associated with advanced disease. TYMS catalyzes the de novo synthesis reaction of deoxythymidine monophosphate (dTMP), one of the building blocks of DNA. Although TYMS inhibitors have served as components of chemotherapy regimens, the currently available inhibitors induce TYMS overexpression or alter folate transport/metabolism feedback pathways that tumor cells exploit for drug resistance limiting overall benefit. Here we report a small molecule TYMS inhibitor and its two analogues that exhibit i) enhanced anti-tumor activity as compared to current fluoropyrimidines and antifolates without inducing TYMS overexpression, ii) are structurally distinct from classical antifolates, iii) extend survival in both pancreatic xenograft tumor models and hTS/Ink4a/Arf null genetically engineered mouse tumor model, iv) and are well tolerated with equal efficacy using either intraperitoneal or oral administration. Mechanistically, we confirm the compound and its analogues are a multifunctional non-classical antifolate, and we identify structural features allowing direct TYMS inhibition while also maintaining the ability to inhibit dihydrofolate reductase (DHFR). Collectively, this work identifies new non-classical antifolate inhibitors that optimize inhibition of thymidylate biosynthesis with a favorable safety profile highlighting potential for enhanced cancer therapy. Citation Format: Peter Elias Dib, Maria Guijarro, Patrick Kellish, Nick Paciaroni, Akbar Nawab, Jacob Andring, Lidia Kulemina, Derek Leas, Nick Borrero, Carlos Modenutti, Richard Bennett, Jonathan Licht, Robert McKenna, Adrian Roitberg, Frederic Kaye, Maria Zajac-Kaye. Discovery of a first-in-class multifunctional TYMS non-classical antifolate inhibitors with potent in vivo activity that prolongs survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1657.
Type of Medium:
Online Resource
ISSN:
1538-7445
DOI:
10.1158/1538-7445.AM2023-1657
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2023
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
