ArticleCell chemical biology2023
Inducible mismatch repair streamlines forward genetic approaches to target identification of cytotoxic small molecules.
Article in Cell chemical biology, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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9 citing papers in PubMed.
- A selective NVL inhibitor suppresses tumor growth by targeting ribosome biogenesis.Nature chemical biology · 2026Article
- Positive selection screen identifies natural product β-catenin inactivators.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Ultramutagenesis through Combined Msh2 Depletion and Proofreading-Deficient DNA Polymerase ε Expression Enhances Small-Molecule Target Identification in Forward Genetic Screens.ACS chemical biology · 2026Article
- Triptolide sensitizes cancer cells to nucleoside DNA methyltransferase inhibitors through inhibition of DCTPP1-mediated cell-intrinsic resistance.Nature communications · 2026Article
- Ultramutagenesis through combined Msh2 depletion and proofreading-deficient DNA polymerase ε expression enhances small molecule target identification in forward genetic screens.bioRxiv : the preprint server for biology · 2026Article
- Article
- Thiophenyl Derivatives of Nicotinamide Are Metabolized by the NAD Salvage Pathway into Unnatural NAD Derivatives That Inhibit IMPDH and Are Toxic to Peripheral Nerve Cancers.ACS chemical biology · 2024Article
- Forward Genetic Screens Identify Mechanisms of Resistance to Small-Molecule Lactate Dehydrogenase Inhibitors.ACS chemical biology · 2024Article
- Anticancer benzoxaboroles block pre-mRNA processing by directly inhibiting CPSF3.Cell chemical biology · 2024Article
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Abstract
Orphan cytotoxins are small molecules for which the mechanism of action (MoA) is either unknown or ambiguous. Unveiling the mechanism of these compounds may lead to useful tools for biological investigation and new therapeutic leads. In selected cases, the DNA mismatch repair-deficient colorectal cancer cell line, HCT116, has been used as a tool in forward genetic screens to identify compound-resistant mutations, which have ultimately led to target identification. To expand the utility of this approach, we engineered cancer cell lines with inducible mismatch repair deficits, thus providing temporal control over mutagenesis. By screening for compound resistance phenotypes in cells with low or high rates of mutagenesis, we increased both the specificity and sensitivity of identifying resistance mutations. Using this inducible mutagenesis system, we implicate targets for multiple orphan cytotoxins, including a natural product and compounds emerging from a high-throughput screen, thus providing a robust tool for future MoA studies.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.