Therapeutic disruption of RAD52–ssDNA complexation via novel drug-like inhibitors

Divya S Bhat; Eva Malacaria; Ludovica Di Biagi; Mortezaali Razzaghi; Masayoshi Honda; Kathryn F Hobbs; Sarah R Hengel; Pietro Pichierri; M Ashley Spies; Maria Spies

doi:10.1093/narcan/zcad018

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Therapeutic disruption of RAD52–ssDNA complexation via novel drug-like inhibitors

Journal article

Open access

Therapeutic disruption of RAD52–ssDNA complexation via novel drug-like inhibitors

Divya S Bhat, Eva Malacaria, Ludovica Di Biagi, Mortezaali Razzaghi, Masayoshi Honda, Kathryn F Hobbs, Sarah R Hengel, Pietro Pichierri, M Ashley Spies and Maria Spies

NAR cancer, Vol.5(2), zcad018

06/2023

DOI: 10.1093/narcan/zcad018

PMCID: PMC10150327

PMID: 37139244

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Abstract

RAD52 protein is a coveted target for anticancer drug discovery. Similar to poly-ADP-ribose polymerase (PARP) inhibitors, pharmacological inhibition of RAD52 is synthetically lethal with defects in genome caretakers BRCA1 and BRCA2 (∼25% of breast and ovarian cancers). Emerging structure activity relationships for RAD52 are complex, making it challenging to transform previously identified disruptors of the RAD52–ssDNA interaction into drug-like leads using traditional medicinal chemistry approaches. Using pharmacophoric informatics on the RAD52 complexation by epigallocatechin (EGC), and the Enamine in silico REAL database, we identified six distinct chemical scaffolds that occupy the same physical space on RAD52 as EGC. All six were RAD52 inhibitors (IC 50 ∼23–1200 μM) with two of the compounds (Z56 and Z99) selectively killing BRCA-mutant cells and inhibiting cellular activities of RAD52 at micromolar inhibitor concentrations. While Z56 had no effect on the ssDNA-binding protein RPA and was toxic to BRCA-mutant cells only, Z99 inhibited both proteins and displayed toxicity towards BRCA-complemented cells. Optimization of the Z99 scaffold resulted in a set of more powerful and selective inhibitors (IC 50 ∼1.3–8 μM), which were only toxic to BRCA-mutant cells. RAD52 complexation by Z56, Z99 and its more specific derivatives provide a roadmap for next generation of cancer therapeutics. Graphical Abstract Exploration of the Enamine in silico REAL space of billions of potential compounds yielded new drug-like inhibitors of the DNA repair protein RAD52. The compounds were further optimized to improve efficacy and specificity in targeting RAD52 in vitro and killing BRCA1 and BRCA2 deficient cancer cells.

AcademicSubjects

DNA Damage Sensing and Repair

SCI00030

SCI00980

SCI01060

SCI01140

SCI01180

Details

Title: Subtitle: Therapeutic disruption of RAD52–ssDNA complexation via novel drug-like inhibitors
Creators: Divya S Bhat - , , , IA
Eva Malacaria - Istituto Superiore di Sanità
Ludovica Di Biagi - Istituto Superiore di Sanità
Mortezaali Razzaghi - University of Iowa
Masayoshi Honda - University of Iowa
Kathryn F Hobbs - University of Iowa
Sarah R Hengel - University of Iowa
Pietro Pichierri - Istituto Superiore di Sanità
M Ashley Spies - , , , IA , , , 52242, , 401 Mullin Ave., , 52246
Maria Spies - University of Iowa
Resource Type: Journal article
Publication Details: NAR cancer, Vol.5(2), zcad018
DOI: 10.1093/narcan/zcad018
PMID: 37139244
PMCID: PMC10150327
NLM abbreviation: NAR Cancer
ISSN: 2632-8674
eISSN: 2632-8674
Publisher: Oxford University Press
Grant note: ; T32 GM008365 / ; T32 CA078586 / ; R01 CA232425; R01 GM09737; R01 GM138471 / ;
Language: English
Date published: 06/2023
Academic Unit: Pharmaceutical Sciences and Experimental Therapeutics; Radiation Oncology; Biochemistry and Molecular Biology; Medicinal and Natural Products Chemistry
Record Identifier: 9984400755502771

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