{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T12:07:49Z","timestamp":1793275669428,"version":"4.5.0"},"reference-count":93,"publisher":"American Chemical Society (ACS)","issue":"33","license":[{"start":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T00:00:00Z","timestamp":1786665600000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T00:00:00Z","timestamp":1786665600000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T00:00:00Z","timestamp":1786665600000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-045"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01GM144471"],"award-info":[{"award-number":["R01GM144471"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["S10OD034245"],"award-info":[{"award-number":["S10OD034245"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100022871","name":"National Defense Medical Center","doi-asserted-by":"publisher","award":["NA"],"award-info":[{"award-number":["NA"]}],"id":[{"id":"10.13039\/100022871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100027426","name":"Schmidt Futures","doi-asserted-by":"publisher","award":["NA"],"award-info":[{"award-number":["NA"]}],"id":[{"id":"10.13039\/100027426","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,8,26]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Natural products (NPs) are foundational to drug discovery, owing to their diverse molecular scaffolds and novel bioactivities. However, optimizing NPs for optimal bioactivity and improved drug properties is hindered by material scarcity and labor-intensive purification processes. Here, we present an automated ultrahigh-throughput experimentation (ultraHTE) and direct-to-biology (D2B) platform that enables rapid structure\u2013activity relationship (SAR) mapping from miniaturized libraries of synthetic NP analogues, unlocking NPs as a viable starting point for late-stage diversification in drug-lead optimization. Starting from leelamine, a conifer resin-derived tricyclic diterpene with prostate cancer antiproliferative activity, we synthesized leelamine analogues in a 1536-well format, achieving a 73% success rate while consuming only 0.03 mg of NP per reaction. Key to success was the development of a platinum-catalyzed amine\u2013acid reductive amination reaction, which performed well on both amine and complementary acid-derived NPs, in a so-called Janus strategy which more than doubled the accessible chemical space. Direct phenotypic screening in LNCaP cells enabled rapid identification of potent, cell-permeable analogues with robust quality control achieved through iterative resynthesis on preparative scale. SAR insights revealed two key substitution patterns driving potency based on 4-methoxyphenyl and 3-indolyl derivatives. Mechanistic studies\u2500including androgen receptor binding, chemoproteomics, and a lysosomal cholesterol colocalization assay\u2500demonstrated distinct modes of action for optimized analogues compared to leelamine. Collectively, this amine\u2013acid amination-based D2B platform showcases accelerated SAR elucidation from minimal material and cellular profiling, unlocking a framework for mechanism-driven lead discovery in NP chemical space.<\/jats:p>","DOI":"10.1021\/jacs.6c06623","type":"journal-article","created":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T22:01:45Z","timestamp":1786744905000},"page":"35515-35528","source":"Crossref","is-referenced-by-count":2,"title":["A Direct-to-Biology\nAmine\u2013Acid Amination for\nRapid Phenotypic Profiling of Lysosomotropic Natural Products"],"prefix":"10.1021","volume":"148","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5804-2471","authenticated-orcid":true,"given":"Yu-Ting","family":"Kao","sequence":"first","affiliation":[{"name":"University of Michigan , , , ,","place":["Ann Arbor, Michigan, United States, 48109"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamed","family":"Abdelalim","sequence":"additional","affiliation":[{"name":"University of Michigan , , , ,","place":["Ann Arbor, Michigan, United States, 48109"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-5714-0895","authenticated-orcid":true,"given":"Carl","family":"Mauro","sequence":"additional","affiliation":[{"name":"University of Michigan , , , ,","place":["Ann Arbor, Michigan, United States, 48109"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4478-9010","authenticated-orcid":true,"given":"James L.","family":"Douthwaite","sequence":"additional","affiliation":[{"name":"University of Michigan , , , ,","place":["Ann Arbor, Michigan, United States, 48109"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9275-0017","authenticated-orcid":true,"given":"Andrew","family":"McGrath","sequence":"additional","affiliation":[{"name":"University of Michigan , , , ,","place":["Ann Arbor, Michigan, United States, 48109"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophia R.","family":"Meyer","sequence":"additional","affiliation":[{"name":"University of Michigan , , , ,","place":["Ann Arbor, Michigan, United States, 48109"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Santanu","family":"Singha","sequence":"additional","affiliation":[{"name":"University of Michigan , , , ,","place":["Ann Arbor, Michigan, United States, 48109"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diana","family":"Flores Diaz","sequence":"additional","affiliation":[{"name":"University of Michigan Medical School , , , ,","place":["Ann Arbor, Michigan, United States, 48109"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mi","family":"Wang","sequence":"additional","affiliation":[{"name":"University of Michigan Medical School , , , ,","place":["Ann Arbor, Michigan, United States, 48109"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8782-6950","authenticated-orcid":true,"given":"Shaomeng","family":"Wang","sequence":"additional","affiliation":[{"name":"University of Michigan , , , ,","place":["Ann Arbor, Michigan, United States, 48109"]},{"name":"University of Michigan Medical School , , , ,","place":["Ann Arbor, Michigan, United States, 48109"]},{"name":"University of Michigan , , , ,","place":["Ann Arbor, Michigan, United States, 48109"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan Z.","family":"Sexton","sequence":"additional","affiliation":[{"name":"University of Michigan , , , ,","place":["Ann Arbor, Michigan, United States, 48109"]},{"name":"University of Michigan Medical School , , , ,","place":["Ann Arbor, Michigan, United States, 48109"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5407-0643","authenticated-orcid":true,"given":"Tim","family":"Cernak","sequence":"additional","affiliation":[{"name":"University of Michigan , , , ,","place":["Ann Arbor, Michigan, United States, 48109"]},{"name":"University of Michigan , , , ,","place":["Ann Arbor, Michigan, United States, 48109"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,14]]},"reference":[{"issue":"3","key":"2026090104514351000_cit1","doi-asserted-by":"publisher","first-page":"770","DOI":"10.1021\/acs.jnatprod.9b01285","article-title":"Natural Products as Sources of New Drugs over the Nearly\nFour Decades from 01\/1981 to 09\/2019","volume":"83","author":"Newman","year":"2020","journal-title":"J. Nat.\nProd."},{"issue":"3","key":"2026090104514351000_cit2","doi-asserted-by":"publisher","first-page":"353","DOI":"10.1039\/D0MD00376J","article-title":"Natural Product-Informed Exploration\nof Chemical Space\nto Enable Bioactive Molecular Discovery","volume":"12","author":"Nelson","year":"2021","journal-title":"RSC\nMed. Chem."},{"issue":"5","key":"2026090104514351000_cit3","doi-asserted-by":"publisher","first-page":"622","DOI":"10.1021\/acscentsci.9b00916","article-title":"Late-Stage Diversification of Natural Products","volume":"6","author":"Hong","year":"2020","journal-title":"ACS Cent. Sci."},{"issue":"3","key":"2026090104514351000_cit4","doi-asserted-by":"publisher","first-page":"1030","DOI":"10.1016\/j.apsb.2023.11.021","article-title":"Late-Stage Modification\nof Bioactive Compounds: Improving\nDruggability through Efficient Molecular Editing","volume":"14","author":"Huo","year":"2024","journal-title":"Acta Pharm. Sin. B"},{"issue":"3","key":"2026090104514351000_cit5","doi-asserted-by":"publisher","first-page":"200","DOI":"10.1038\/s41573-020-00114-z","article-title":"Natural Products in\nDrug Discovery: Advances and Opportunities","volume":"20","author":"the International Natural Product Sciences Taskforce","year":"2021","journal-title":"Nat. Rev. Drug Discovery"},{"issue":"6","key":"2026090104514351000_cit6","doi-asserted-by":"publisher","first-page":"531","DOI":"10.1038\/nchem.2479","article-title":"Counting on\nNatural Products for Drug Design","volume":"8","author":"Rodrigues","year":"2016","journal-title":"Nat. Chem."},{"issue":"6","key":"2026090104514351000_cit7","doi-asserted-by":"publisher","first-page":"4180","DOI":"10.1021\/acs.chemrev.8b00504","article-title":"Structural\nSimplification of Natural\nProducts","volume":"119","author":"Wang","year":"2019","journal-title":"Chem. Rev."},{"issue":"1","key":"2026090104514351000_cit8","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-39531-0","article-title":"Rapid Planning\nand Analysis of High-Throughput\nExperiment Arrays for Reaction Discovery","volume":"14","author":"Mahjour","year":"2023","journal-title":"Nat.\nCommun."},{"issue":"9","key":"2026090104514351000_cit9","doi-asserted-by":"publisher","first-page":"3594","DOI":"10.1021\/acs.jmedchem.6b01543","article-title":"Microscale High-Throughput Experimentation\nas an Enabling Technology in Drug Discovery: Application in the Discovery\nof (Piperidinyl)Pyridinyl-1 H -Benzimidazole Diacylglycerol\nAcyltransferase 1 Inhibitors","volume":"60","author":"Cernak","year":"2017","journal-title":"J. Med. Chem."},{"issue":"6217","key":"2026090104514351000_cit10","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1126\/science.1259203","article-title":"Nanomole-Scale High-Throughput Chemistry\nfor the Synthesis of Complex Molecules","volume":"347","author":"Buitrago Santanilla","year":"2015","journal-title":"Science"},{"issue":"11","key":"2026090104514351000_cit11","doi-asserted-by":"publisher","first-page":"1082","DOI":"10.1038\/s44160-023-00351-1","article-title":"Miniaturization of Popular Reactions\nfrom the Medicinal Chemists\u2019 Toolbox for Ultrahigh-Throughput\nExperimentation","volume":"2","author":"Gesmundo","year":"2023","journal-title":"Nat. Synth."},{"issue":"10","key":"2026090104514351000_cit12","doi-asserted-by":"publisher","first-page":"2337","DOI":"10.1021\/acs.accounts.1c00119","article-title":"Ultrahigh-Throughput\nExperimentation\nfor Information-Rich Chemical Synthesis","volume":"54","author":"Mahjour","year":"2021","journal-title":"Acc.\nChem. Res."},{"issue":"1","key":"2026090104514351000_cit13","doi-asserted-by":"publisher","DOI":"10.1038\/s43586-021-00022-5","article-title":"Automation and Computer-Assisted\nPlanning for Chemical\nSynthesis","volume":"1","author":"Shen","year":"2021","journal-title":"Nat. Rev. Methods Primers"},{"issue":"7704","key":"2026090104514351000_cit14","doi-asserted-by":"publisher","first-page":"228","DOI":"10.1038\/s41586-018-0056-8","article-title":"Nanoscale Synthesis and Affinity\nRanking","volume":"557","author":"Gesmundo","year":"2018","journal-title":"Nature"},{"key":"2026090104514351000_cit15","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.4c00807","article-title":"Late-Stage\nSaturation\nof Drug Molecules","volume":"146","author":"Liu","year":"2024","journal-title":"J. Am. Chem. Soc."},{"issue":"1","key":"2026090104514351000_cit16","doi-asserted-by":"publisher","DOI":"10.1038\/s42004-024-01101-w","article-title":"Exploring\nthe Combinatorial\nExplosion of Amine\u2013Acid Reaction Space via Graph Editing","volume":"7","author":"Zhang","year":"2024","journal-title":"Commun. Chem."},{"issue":"20","key":"2026090104514351000_cit17","doi-asserted-by":"publisher","first-page":"10930","DOI":"10.1021\/jacs.2c11563","article-title":"Formal Cross-Coupling of Amines and\nCarboxylic Acids\nto Form Sp 3 \u2013 Sp 2 Carbon\u2013Carbon\nBonds","volume":"145","author":"Douthwaite","year":"2023","journal-title":"J. Am. Chem. Soc."},{"issue":"7801","key":"2026090104514351000_cit18","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1038\/s41586-020-2142-y","article-title":"A Map of the Amine\u2013Carboxylic\nAcid Coupling System","volume":"580","author":"Mahjour","year":"2020","journal-title":"Nature"},{"issue":"8","key":"2026090104514351000_cit19","doi-asserted-by":"publisher","first-page":"1026","DOI":"10.1039\/D2CC05670D","article-title":"Repurposing Amine and\nCarboxylic Acid Building Blocks with an Automatable Esterification\nReaction","volume":"59","author":"McGrath","year":"2023","journal-title":"Chem. Commun."},{"issue":"1","key":"2026090104514351000_cit20","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1021\/acs.jmedchem.4c02047","article-title":"Modulating the Potency\nof BRD4 PROTACs\nat the Systems Level with Amine-Acid Coupling Reactions","volume":"68","author":"McGrath","year":"2025","journal-title":"J. Med. Chem."},{"issue":"1","key":"2026090104514351000_cit21","doi-asserted-by":"publisher","DOI":"10.1038\/s42004-022-00698-0","article-title":"Development\nof Copper-Catalyzed Deaminative\nEsterification Using High-Throughput Experimentation","volume":"5","author":"Shen","year":"2022","journal-title":"Commun. Chem."},{"issue":"52","key":"2026090104514351000_cit22","doi-asserted-by":"publisher","first-page":"27293","DOI":"10.1002\/anie.202112454","article-title":"The Formal Cross-Coupling of Amines\nand Carboxylic\nAcids to Form Sp 3 \u2013 Sp 3 Carbon\u2013Carbon\nBonds","volume":"60","author":"Zhang","year":"2021","journal-title":"Angew. Chem., Int. Ed"},{"issue":"8","key":"2026090104514351000_cit23","doi-asserted-by":"publisher","first-page":"9142","DOI":"10.1021\/acs.jmedchem.5c03614","article-title":"Nanoscale\nDirect-to-Biology Optimization of\nCdk2 Inhibitors","volume":"69","author":"Douthwaite","year":"2026","journal-title":"J. Med. Chem."},{"issue":"10","key":"2026090104514351000_cit24","doi-asserted-by":"publisher","first-page":"2079","DOI":"10.1158\/1535-7163.MCT-18-0117","article-title":"Therapeutic Potential of Leelamine, a Novel Inhibitor\nof Androgen Receptor and Castration-Resistant Prostate Cancer","volume":"17","author":"Singh","year":"2018","journal-title":"Mol. Cancer Ther."},{"issue":"7","key":"2026090104514351000_cit25","doi-asserted-by":"publisher","first-page":"1679","DOI":"10.1158\/1535-7163.MCT-13-0867","article-title":"Targeting\nMultiple Key Signaling Pathways in Melanoma Using Leelamine","volume":"13","author":"Gowda","year":"2014","journal-title":"Mol. Cancer Ther."},{"issue":"7","key":"2026090104514351000_cit26","doi-asserted-by":"publisher","first-page":"1690","DOI":"10.1158\/1535-7163.MCT-13-0868","article-title":"Leelamine\nMediates Cancer Cell Death through Inhibition of Intracellular Cholesterol\nTransport","volume":"13","author":"Kuzu","year":"2014","journal-title":"Mol. Cancer Ther."},{"issue":"10","key":"2026090104514351000_cit27","doi-asserted-by":"publisher","first-page":"1800","DOI":"10.1158\/1535-7163.MCT-19-0046","article-title":"Leelamine Is a Novel\nLipogenesis Inhibitor in Prostate Cancer Cells In Vitro and In Vivo","volume":"18","author":"Singh","year":"2019","journal-title":"Mol. Cancer\nTher."},{"issue":"2","key":"2026090104514351000_cit28","doi-asserted-by":"publisher","first-page":"314","DOI":"10.1158\/1541-7786.MCR-07-0354","article-title":"Sterol Regulatory Element\u2013Binding\nProtein-1c Represses the\nTransactivation of Androgen Receptor and Androgen-Dependent Growth\nof Prostatic Cells","volume":"6","author":"Suh","year":"2008","journal-title":"Molecular Cancer Research"},{"issue":"8","key":"2026090104514351000_cit29","doi-asserted-by":"publisher","first-page":"1250","DOI":"10.1038\/s41416-024-02762-z","article-title":"Metabolic Adaptations in Prostate\nCancer","volume":"131","author":"Pujana-Vaquerizo","year":"2024","journal-title":"Br. J. Cancer"},{"issue":"1","key":"2026090104514351000_cit30","doi-asserted-by":"publisher","DOI":"10.1186\/s12944-024-02024-0","article-title":"Reprogramming of Lipid Metabolism\nin the Tumor Microenvironment: A Strategy for Tumor Immunotherapy","volume":"23","author":"Wu","year":"2024","journal-title":"Lipids Health Dis"},{"issue":"1","key":"2026090104514351000_cit31","doi-asserted-by":"publisher","DOI":"10.1186\/s13045-023-01498-2","article-title":"Lipid Metabolic\nReprogramming in\nTumor Microenvironment: From Mechanisms to Therapeutics","volume":"16","author":"Jin","year":"2023","journal-title":"J. Hematol. Oncol."},{"issue":"17","key":"2026090104514351000_cit32","doi-asserted-by":"publisher","first-page":"28260","DOI":"10.18632\/oncotarget.16002","article-title":"Identifying\nthe Structure-Activity Relationship of Leelamine Necessary for Inhibiting\nIntracellular Cholesterol Transport","volume":"8","author":"Gowda","year":"2017","journal-title":"Oncotarget"},{"issue":"12","key":"2026090104514351000_cit33","doi-asserted-by":"publisher","first-page":"4743","DOI":"10.3390\/molecules28124743","article-title":"Tricyclic Diterpenoids\nSelectively Suppress Androgen Receptor-Positive Prostate Cancer Cells","volume":"28","author":"Sekhon","year":"2023","journal-title":"Molecules"},{"key":"2026090104514351000_cit34","doi-asserted-by":"publisher","first-page":"333","DOI":"10.1016\/B978-0-323-96025-0.00174-5","article-title":"Direct-To-Biology\nChemistry","volume-title":"Comprehensive Organic Synthesis","author":"Kao","year":"2025"},{"issue":"58","key":"2026090104514351000_cit35","doi-asserted-by":"publisher","first-page":"8047","DOI":"10.1039\/D0CC02361B","article-title":"Activity-Directed Expansion\nof a Series of Antibacterial\nAgents","volume":"56","author":"Leggott","year":"2020","journal-title":"Chem. Commun."},{"key":"2026090104514351000_cit36","doi-asserted-by":"publisher","DOI":"10.1016\/j.aca.2021.338950","article-title":"Nanomole-Scaled\nHigh-Throughput Chemistry plus Direct\nBioautography on the Same Chromatography Plate for Drug Discovery","volume":"1182","author":"Yu\u0308ce","year":"2021","journal-title":"Anal. Chim. Acta"},{"issue":"48","key":"2026090104514351000_cit37","doi-asserted-by":"publisher","first-page":"9672","DOI":"10.1039\/D2OB01404A","article-title":"Algorithm-Driven Activity-Directed\nExpansion of a Series of Antibacterial Quinazolinones","volume":"20","author":"Francis","year":"2022","journal-title":"Org. Biomol. Chem."},{"issue":"15","key":"2026090104514351000_cit38","doi-asserted-by":"publisher","first-page":"10341","DOI":"10.1021\/acs.jmedchem.1c02206","article-title":"Optimization\nof Covalent MKK7 Inhibitors via Crude Nanomole-Scale\nLibraries","volume":"65","author":"Gehrtz","year":"2022","journal-title":"J. Med. Chem."},{"key":"2026090104514351000_cit39","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2022.114421","article-title":"Identification and Development of\na Series of Disubstituted\nPiperazines for the Treatment of Chagas Disease","volume":"238","author":"McGonagle","year":"2022","journal-title":"Eur. J. Med. Chem."},{"issue":"35","key":"2026090104514351000_cit40","doi-asserted-by":"publisher","DOI":"10.1002\/ange.202206516","article-title":"Selenylation Chemistry Suitable for On-Plate Parallel and On-DNA\nLibrary Synthesis Enabling High-Throughput Medicinal Chemistry","volume":"134","author":"Xu","year":"2022","journal-title":"Angew. Chem."},{"issue":"1","key":"2026090104514351000_cit41","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-43614-3","article-title":"Direct-to-Biology,\nAutomated, Nano-Scale Synthesis, and Phenotypic Screening-Enabled\nE3 Ligase Modulator Discovery","volume":"14","author":"Wang","year":"2023","journal-title":"Nat. Commun."},{"issue":"31","key":"2026090104514351000_cit42","doi-asserted-by":"publisher","DOI":"10.1002\/ange.202424118","article-title":"Solid-Phase Parallel Synthesis of Photocleavable Bifunctional Molecules\nEnables Efficient Phenotypic Protein Degrader Discovery","volume":"137","author":"Ding","year":"2025","journal-title":"Angew. Chem."},{"issue":"1","key":"2026090104514351000_cit43","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-16920-3","article-title":"Ultra-Large\nChemical Libraries for the Discovery of High-Affinity Peptide Binders","volume":"11","author":"Quartararo","year":"2020","journal-title":"Nat. Commun."},{"key":"2026090104514351000_cit44","doi-asserted-by":"publisher","first-page":"8961","DOI":"10.1021\/acs.jmedchem.2c00154","article-title":"Accelerated Identification\nof Cell Active KRAS Inhibitory Macrocyclic\nPeptides Using Mixture Libraries and Automated Ligand Identification\nSystem (ALIS) Technology","volume":"65","author":"Garrigou","year":"2022","journal-title":"J. Med. Chem."},{"issue":"1","key":"2026090104514351000_cit45","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-025-65282-1","article-title":"Barcode-Free Hit Discovery from Massive Libraries Enabled\nby Automated Small Molecule Structure Annotation","volume":"16","author":"Van Der Nol","year":"2025","journal-title":"Nat. Commun."},{"issue":"11","key":"2026090104514351000_cit46","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2220767120","article-title":"Affinity Selection\nof Double-Click\nTriazole Libraries for Rapid Discovery of Allosteric Modulators for\nGLP-1 Receptor","volume":"120","author":"Xin","year":"2023","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"issue":"6","key":"2026090104514351000_cit47","doi-asserted-by":"publisher","first-page":"2271","DOI":"10.1021\/acs.jmedchem.6b01478","article-title":"Application of Off-Rate Screening in the Identification of Novel\nPan-Isoform Inhibitors of Pyruvate Dehydrogenase Kinase","volume":"60","author":"Brough","year":"2017","journal-title":"J. Med. Chem."},{"issue":"7","key":"2026090104514351000_cit48","doi-asserted-by":"publisher","first-page":"2845","DOI":"10.1021\/jm401848a","article-title":"Off-Rate Screening\n(ORS) By Surface Plasmon Resonance. An Efficient Method to Kinetically\nSample Hit to Lead Chemical Space from Unpurified Reaction Products","volume":"57","author":"Murray","year":"2014","journal-title":"J. Med. Chem."},{"issue":"6","key":"2026090104514351000_cit49","doi-asserted-by":"publisher","first-page":"1487","DOI":"10.1021\/acschembio.0c00140","article-title":"Two-Stage\nStrategy for Development of Proteolysis Targeting\nChimeras and Its Application for Estrogen Receptor Degraders","volume":"15","author":"Roberts","year":"2020","journal-title":"ACS Chem. Biol."},{"key":"2026090104514351000_cit50","doi-asserted-by":"publisher","first-page":"1182","DOI":"10.1021\/acsmedchemlett.2c00124","article-title":"Direct-to-Biology Accelerates PROTAC\nSynthesis and\nthe Evaluation of Linker Effects on Permeability and Degradation","volume":"13","author":"Hendrick","year":"2022","journal-title":"ACS Med. Chem. 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