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- W4366091440 abstract "PIP-199 is the only reported small molecule inhibitor of FANCM-RMI, a key protein-protein interaction that governs genome instability in the genetic disorders Fanconi Anemia and Bloom’s Syndrome. PIP-199 and close analogues that share the same indole-derived Mannich base core scaffold have been used as commercially available tool compounds for studying a wide range of therapeutically relevant biological pathways and targets, including the Alternative Lengthening of Telomeres (ALT), G-quadruplexes, pro-apoptotic proteins, and quorum sensing. Herein, we report the first published synthesis of PIP-199 and related analogues, demonstrating that the parent compound immediately decomposes in common aqueous buffers and some organic solvents. We characterize the breakdown products and show that PIP-199 and its more hydrolytically stable analogues show no observable activity in binding and competitive biophysical assays for FANCM-RMI. We conclude that PIP-199 is not an effective tool compound for biological studies, and that apparent activity in cellular studies likely arises from non-specific toxicity of mixed breakdown products. More generally, apparent inhibitors that share this indole-derived Mannich scaffold potentially represent a new family of pan-assay interference compounds (PAINS) that should be thoroughly assessed for aqueous stability prior to use in biological studies." @default.
- W4366091440 created "2023-04-19" @default.
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- W4366091440 date "2023-04-17" @default.
- W4366091440 modified "2023-09-26" @default.
- W4366091440 title "Mannich base PIP-199 is a chemically unstable pan-assay interference compound" @default.
- W4366091440 doi "https://doi.org/10.26434/chemrxiv-2023-60glz-v2" @default.
- W4366091440 hasPublicationYear "2023" @default.
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