Serendipity meets synergism: differential enantiomer activities of a RAD51-BRCA2 disruptor towards a more robust synthetic lethality in pancreatic cancer

Serendipity meets synergism: differential enantiomer activities of a RAD51-BRCA2 disruptor towards a more robust synthetic lethality in pancreatic cancer | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Serendipity meets synergism: differential enantiomer activities of a RAD51-BRCA2 disruptor towards a more robust synthetic lethality in pancreatic cancer Stefania Girotto, Mirco Masi, Laura Poppi, Viola Previtali, Shannon Nelson, and 15 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4031427/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract The innovative framework of a fully small molecule-induced synthetic lethality gained increasing attention for its promising application in the selective eradication of cancer cells. Disrupting the interaction between BRCA2 and RAD51, key players in DNA repair by homologous recombination (HR), represents an interesting option within the synthetic lethality paradigm. We previously showed that combining the PARP inhibitor (PARPi) olaparib with the BRCA2-RAD51 disruptor RS-35d , a racemic dihydroquinolone pyrazoline-derivative previously synthetized by us, was efficient in tackling pancreatic ductal adenocarcinoma (PDAC). To deepen our knowledge on this approach, we investigated RS-35d mode of action by characterising the single contribution of the purified two enantiomers, R-35d and S-35d respectively. RS-35d racemate was unveiled to possess a built-in synthetic lethal profile, falling within the paradigm of “within-pathway synthetic lethality”. This opens the way for novel anticancer synthetic lethality strategies towards more robust personalised medicine approaches for unmet medical needs like BRCA-competent and PARP-resistant PDAC. Biological sciences/Chemical biology/Small molecules Biological sciences/Cancer/Cancer therapy Biological sciences/Drug discovery/Pharmacology Anticancer drugs Homologous recombination PARP inhibitors Protein-protein small molecule inhibitors PARPi resistance Full Text Additional Declarations Yes there is potential Competing Interest. VP, FDF, JAO, GB, RP, GDS, MR and ACa are co-inventors on a patent application (WO 2021/116999 A1, “Compounds and compositions for the treatment of tumors”, PCT/IB2020/061825) protecting the compound(s) disclosed in this article. Supplementary Files MasiMetalNatChemBiolSupplementaryData.pdf Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4031427","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":278006131,"identity":"61e497ed-da63-40f1-9f44-8bd0de6699ef","order_by":0,"name":"Stefania 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Disrupting the interaction between BRCA2 and RAD51, key players in DNA repair by homologous recombination (HR), represents an interesting option within the synthetic lethality paradigm. We previously showed that combining the PARP inhibitor (PARPi) olaparib with the BRCA2-RAD51 disruptor \u003cem\u003e\u003cstrong\u003eRS-35d\u003c/strong\u003e\u003c/em\u003e, a racemic dihydroquinolone pyrazoline-derivative previously synthetized by us, was efficient in tackling pancreatic ductal adenocarcinoma (PDAC). To deepen our knowledge on this approach, we investigated \u003cem\u003e\u003cstrong\u003eRS-35d\u003c/strong\u003e\u003c/em\u003e mode of action by characterising the single contribution of the purified two enantiomers, \u003cem\u003e\u003cstrong\u003eR-35d\u003c/strong\u003e\u003c/em\u003e and \u003cem\u003e\u003cstrong\u003eS-35d\u003c/strong\u003e\u003c/em\u003e respectively. \u003cem\u003e\u003cstrong\u003eRS-35d\u003c/strong\u003e\u003c/em\u003e racemate was unveiled to possess a built-in synthetic lethal profile, falling within the paradigm of “within-pathway synthetic lethality”. 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