PMID- 32364710 OWN - NLM STAT- MEDLINE DCOM- 20210413 LR - 20230929 IS - 1520-5126 (Electronic) IS - 0002-7863 (Print) IS - 0002-7863 (Linking) VI - 142 IP - 19 DP - 2020 May 13 TI - Design, Optimization, and Study of Small Molecules That Target Tau Pre-mRNA and Affect Splicing. PG - 8706-8727 LID - 10.1021/jacs.0c00768 [doi] AB - Approximately 95% of human genes are alternatively spliced, and aberrant splicing events can cause disease. One pre-mRNA that is alternatively spliced and linked to neurodegenerative diseases is tau (microtubule-associated protein tau), which can cause frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) and can contribute to Alzheimer's disease. Here, we describe the design of structure-specific lead small molecules that directly target tau pre-mRNA from sequence. This was followed by hit expansion and analogue synthesis to further improve upon these initial lead molecules. The emergent compounds were assessed for functional activity in a battery of assays, including binding assays and an assay that mimics molecular recognition of tau pre-mRNA by a U1 small nuclear ribonucleoprotein (snRNP) splicing factor. Compounds that emerged from these studies had enhanced potency and selectivity for the target RNA relative to the initial hits, while also having significantly improved drug-like properties. The compounds are shown to directly target tau pre-mRNA in cells, via chemical cross-linking and isolation by pull-down target profiling, and to rescue disease-relevant splicing of tau pre-mRNA in a variety of cellular systems, including primary neurons. More broadly, this study shows that lead, structure-specific compounds can be designed from sequence and then further optimized for their physicochemical properties while at the same time enhancing their activity. FAU - Chen, Jonathan L AU - Chen JL AUID- ORCID: 0000-0001-7907-9732 AD - Department of Chemistry and Neuroscience, The Scripps Research Institute, 130 Scripps Way, Jupiter, Florida 33458, United States. FAU - Zhang, Peiyuan AU - Zhang P AD - Department of Chemistry and Neuroscience, The Scripps Research Institute, 130 Scripps Way, Jupiter, Florida 33458, United States. FAU - Abe, Masahito AU - Abe M AD - Department of Chemistry and Neuroscience, The Scripps Research Institute, 130 Scripps Way, Jupiter, Florida 33458, United States. FAU - Aikawa, Haruo AU - Aikawa H AD - Department of Chemistry and Neuroscience, The Scripps Research Institute, 130 Scripps Way, Jupiter, Florida 33458, United States. FAU - Zhang, Liying AU - Zhang L AD - Pfizer Worldwide Research and Development, Cambridge, Massachusetts 02139, United States. FAU - Frank, Alexander J AU - Frank AJ AD - Department of Chemistry & Biochemistry, State University of New York at Fredonia, 311 Science Center, Fredonia, New York 14063, United States. FAU - Zembryski, Timothy AU - Zembryski T AD - Department of Chemistry & Biochemistry, State University of New York at Fredonia, 311 Science Center, Fredonia, New York 14063, United States. FAU - Hubbs, Christopher AU - Hubbs C AD - Department of Chemistry and Neuroscience, The Scripps Research Institute, 130 Scripps Way, Jupiter, Florida 33458, United States. FAU - Park, HaJeung AU - Park H AD - Department of Chemistry and Neuroscience, The Scripps Research Institute, 130 Scripps Way, Jupiter, Florida 33458, United States. FAU - Withka, Jane AU - Withka J AD - Pfizer Worldwide Research and Development, Cambridge, Massachusetts 02139, United States. FAU - Steppan, Claire AU - Steppan C AD - Pfizer Worldwide Research and Development, Groton, Connecticut 06340, United States. FAU - Rogers, Lucy AU - Rogers L AD - Pfizer Worldwide Research and Development, Groton, Connecticut 06340, United States. FAU - Cabral, Shawn AU - Cabral S AD - Pfizer Worldwide Research and Development, Groton, Connecticut 06340, United States. FAU - Pettersson, Martin AU - Pettersson M AD - Pfizer Worldwide Research and Development, Cambridge, Massachusetts 02139, United States. FAU - Wager, Travis T AU - Wager TT AD - Pfizer Worldwide Research and Development, Cambridge, Massachusetts 02139, United States. FAU - Fountain, Matthew A AU - Fountain MA AD - Department of Chemistry & Biochemistry, State University of New York at Fredonia, 311 Science Center, Fredonia, New York 14063, United States. FAU - Rumbaugh, Gavin AU - Rumbaugh G AD - Department of Chemistry and Neuroscience, The Scripps Research Institute, 130 Scripps Way, Jupiter, Florida 33458, United States. FAU - Childs-Disney, Jessica L AU - Childs-Disney JL AD - Department of Chemistry and Neuroscience, The Scripps Research Institute, 130 Scripps Way, Jupiter, Florida 33458, United States. FAU - Disney, Matthew D AU - Disney MD AUID- ORCID: 0000-0001-8486-1796 AD - Department of Chemistry and Neuroscience, The Scripps Research Institute, 130 Scripps Way, Jupiter, Florida 33458, United States. LA - eng GR - R01 GM097455/GM/NIGMS NIH HHS/United States GR - RF1 AG062077/AG/NIA NIH HHS/United States GR - P01 NS099114/NS/NINDS NIH HHS/United States GR - DP1 NS096898/NS/NINDS NIH HHS/United States GR - S10 OD021550/OD/NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20200504 PL - United States TA - J Am Chem Soc JT - Journal of the American Chemical Society JID - 7503056 RN - 0 (RNA, Messenger) RN - 0 (Small Molecule Libraries) RN - 0 (tau Proteins) SB - IM MH - HeLa Cells MH - Humans MH - Models, Molecular MH - Molecular Structure MH - RNA Splicing/*drug effects/genetics MH - RNA, Messenger/*antagonists & inhibitors/genetics MH - Small Molecule Libraries/chemical synthesis/chemistry/*pharmacology MH - Thermodynamics MH - tau Proteins/*antagonists & inhibitors/genetics PMC - PMC7357857 MID - NIHMS1606133 COIS- The authors declare the following competing financial interest(s): M.D.D. is a founder of Expansion Therapeutics. Complete contact information is available at: https://pubs.acs.org/10.1021/jacs.0c00768 EDAT- 2020/05/05 06:00 MHDA- 2021/04/14 06:00 PMCR- 2021/05/13 CRDT- 2020/05/05 06:00 PHST- 2020/05/05 06:00 [pubmed] PHST- 2021/04/14 06:00 [medline] PHST- 2020/05/05 06:00 [entrez] PHST- 2021/05/13 00:00 [pmc-release] AID - 10.1021/jacs.0c00768 [doi] PST - ppublish SO - J Am Chem Soc. 2020 May 13;142(19):8706-8727. doi: 10.1021/jacs.0c00768. Epub 2020 May 4.