Escape from planarity in fragment-based drug discovery: A physicochemical and 3D property analysis of synthetic 3D fragment libraries

Lamoree, 2017, Current perspectives in fragment-based lead discovery (FBLD), Essays Biochem, 61, 453, 10.1042/EBC20170028 Erlanson, 2020, Fragment-to-lead medicinal chemistry publications in 2018, J Med Chem, 63, 4430, 10.1021/acs.jmedchem.9b01581 Jahnke, 2020, Fragment-to-lead medicinal chemistry publications in 2019, J Med Chem, 63, 15494, 10.1021/acs.jmedchem.0c01608 Bollag, 2012, Vemurafenib: the first drug approved for BRAF-mutant cancer, Nat Rev Drug Discov, 11, 873, 10.1038/nrd3847 Kim, 2016, The discovery of vemurafenib for the treatment of BRAF-mutated metastatic melanoma, Expert Opin Drug Discov, 11, 907, 10.1080/17460441.2016.1201057 Souers, 2013, ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets, Nat Med, 19, 202, 10.1038/nm.3048 Murray, 2019, A successful collaboration between academia, biotech and pharma led to discovery of erdafitinib, a selective FGFR inhibitor recently approved by the FDA, MedChemComm, 10, 1509, 10.1039/C9MD90044F Zhang, 2013, Design and pharmacology of a highly specific dual FMS and KIT kinase inhibitor, Proc Natl Acad Sci, 110, 5689, 10.1073/pnas.1219457110 Tap, 2015, Structure-guided blockade of CSF1R kinase in tenosynovial giant-cell tumor, N Engl J Med, 373, 428, 10.1056/NEJMoa1411366 Erlanson, 2021, Fragments in the clinic: 2020 edition, Pract Fragm Blog Sauer, 2003, Molecular shape diversity of combinatorial libraries: a prerequisite for broad bioactivity, J Chem Inf Comput Sci, 43, 987, 10.1021/ci025599w Hann, 2001, Molecular complexity and its impact on the probability of finding leads for drug discovery, J Chem Inf Comput Sci, 41, 856, 10.1021/ci000403i Meyers, 2016, On the origins of three-dimensionality in drug-like molecules, Future Med Chem, 8, 1753, 10.4155/fmc-2016-0095 Lovering, 2009, Escape from flatland: increasing saturation as an approach to improving clinical success, J Med Chem, 52, 6752, 10.1021/jm901241e Lovering, 2013, Escape from Flatland 2: Complexity and promiscuity, Medchemcomm, 4, 515, 10.1039/c2md20347b Keserű, 2017, What is the future for fragment-based drug discovery?, Future Med Chem, 9, 1457, 10.4155/fmc-2017-0106 Prosser, 2020, Evaluation of 3-dimensionality in approved and experimental drug space, ACS Med Chem Lett, 11, 1292, 10.1021/acsmedchemlett.0c00121 Yan, 2003, Prediction of aqueous solubility of organic compounds based on a 3D structure representation, J Chem Inf Comput Sci, 43, 429, 10.1021/ci025590u Milroy, 2013, Stabilization and inhibition of protein-protein interactions: the 14-3-3 case study, ACS Chem Biol, 8, 27, 10.1021/cb300599t Valenti, 2019, Clinical candidates modulating protein-protein interactions: the fragment-based experience, Eur J Med Chem, 167, 76, 10.1016/j.ejmech.2019.01.084 Johnson, 2019, Evaluating the advantages of using 3D-enriched fragments for targeting BET bromodomains, ACS Med Chem Lett, 10, 1648, 10.1021/acsmedchemlett.9b00414 Morley, 2013, Fragment-based hit identification: thinking in 3D, Drug Discov. Today, 18, 1221, 10.1016/j.drudis.2013.07.011 Walters, 2011, What do medicinal chemists actually make? A 50-year retrospective, J Med Chem, 54, 6405, 10.1021/jm200504p Murray, 2016, Opportunity knocks: organic chemistry for fragment-based drug discovery (FBDD), Angew Chem Int Ed, 55, 488, 10.1002/anie.201506783 Blakemore, 2018, Organic synthesis provides opportunities to transform drug discovery, Nat Chem, 10, 383, 10.1038/s41557-018-0021-z St. Denis, 2021, Fragment-based drug discovery: opportunities for organic synthesis, RSC Med Chem, 10.1039/D0MD00375A Boström, 2018, Expanding the medicinal chemistry synthetic toolbox, Nat Rev Drug Discov, 17, 709, 10.1038/nrd.2018.116 Caplin, 2021, Emergent synthetic methods for the modular advancement of sp3-rich fragments, Chem Sci, 12, 4646, 10.1039/D1SC00161B Kombo, 2013, 3D molecular descriptors important for clinical success, J Chem Inf Model, 53, 327, 10.1021/ci300445e Tajabadi, 2013, Scaffold flatness: reversing the trend, Springer Sci Rev, 1, 141, 10.1007/s40362-013-0014-7 Firth, 2012, Plane of best fit: a novel method to characterize the three-dimensionality of molecules, J Chem Inf Model, 52, 2516, 10.1021/ci300293f Downes, 2020, Design and synthesis of 56 shape‐diverse 3D fragments, Chem A Eur J, 26, 8969, 10.1002/chem.202001123 Morrison, 2020, Expanding medicinal chemistry into 3D space: metallofragments as 3D scaffolds for fragment-based drug discovery, Chem Sci, 11, 1216, 10.1039/C9SC05586J Reddy Guduru, 2018, Synthesis of enantiomerically pure 3-substituted piperazine-2-acetic acid esters as intermediates for library production, J Org Chem, 83, 11777, 10.1021/acs.joc.8b01708 Chamakuri, 2018, Synthesis of enantiomerically pure 6-substituted-piperazine-2-acetic acid esters as intermediates for library production, J Org Chem, 83, 6541, 10.1021/acs.joc.8b00854 Jain, 2019, Synthesis of enantiomerically pure 5-substituted piperazine-2-acetic acid esters as intermediates for library production, J Org Chem, 84, 6040, 10.1021/acs.joc.9b00148 Congreve, 2003, A ‘Rule of Three’ for fragment-based lead discovery?, Drug Discov Today, 8, 876, 10.1016/S1359-6446(03)02831-9 Hung, 2011, Route to three-dimensional fragments using diversity-oriented synthesis, Proc Natl Acad Sci U S A, 108, 6799, 10.1073/pnas.1015271108 Davis, 2013, Copper-catalyzed N-arylation of 2-imidazolines with aryl iodides, J Org Chem, 78, 3470, 10.1021/jo400120r Morgan, 2014, 2-(Aryl-sulfonyl)oxetanes as designer 3-dimensional fragments for fragment screening: synthesis and strategies for functionalisation, Chem Commun, 50, 5203, 10.1039/C3CC46450D Morgan, 2015, Studies on the synthesis, stability and conformation of 2-sulfonyl-oxetane fragments, Org Biomol Chem, 13, 5265, 10.1039/C5OB00549C Foley, 2015, A systematic approach to diverse, lead-like scaffolds from α,α-disubstituted amino acids, Chem Commun, 51, 11174, 10.1039/C5CC03002A Tran, 2015, Synthesis of functionalized 2-isoxazolines as three-dimensional fragments for fragment-based drug discovery, Tetrahedron Lett, 56, 4119, 10.1016/j.tetlet.2015.05.035 Palmer, 2016, Design and synthesis of dihydroisoquinolones for fragment-based drug discovery (FBDD), Org Biomol Chem, 14, 1599, 10.1039/C5OB02461G Prevet, 2016, Microwave-assisted synthesis of functionalized spirohydantoins as 3-D privileged fragments for scouting the chemical space, Tetrahedron Lett, 57, 2888, 10.1016/j.tetlet.2016.05.065 Wang, 2016, Diversity-oriented synthesis as a strategy for fragment evolution against GSK3β, ACS Med Chem Lett, 7, 852, 10.1021/acsmedchemlett.6b00230 Twigg, 2016, Partially saturated bicyclic heteroaromatics as an sp3-enriched fragment collection, Angew Chem Int Ed, 55, 12479, 10.1002/anie.201606496 Prescher, 2017, Construction of a 3D-shaped, natural product like fragment library by fragmentation and diversification of natural products, Bioorgan Med Chem, 25, 921, 10.1016/j.bmc.2016.12.005 Chalyk, 2017, Synthesis of 6-azaspiro[4.3]alkanes: innovative scaffolds for drug discovery, Eur J Org Chem, 2017, 4530, 10.1002/ejoc.201700536 Chawner, 2017, Divergent synthesis of cyclopropane-containing lead-like compounds, fragments and building blocks through a cobalt catalyzed cyclopropanation of phenyl vinyl sulfide, Eur J Org Chem, 2017, 5015, 10.1002/ejoc.201701030 Hassan, 2018, Design and synthesis of a fragment set based on twisted bicyclic lactams, Bioorganic Med Chem, 26, 3030, 10.1016/j.bmc.2018.02.027 Mateu, 2018, Synthesis of structurally diverse N-substituted quaternary-carbon-containing small molecules from α,α-disubstituted propargyl amino esters, Chem A Eur J, 24, 13681, 10.1002/chem.201803143 Garner, 2019, Design and synthesis of pyrrolidine-based fragments that sample three-dimensional molecular space, ACS Med Chem Lett, 10, 811, 10.1021/acsmedchemlett.9b00070 Zhang, 2019, Construction of a shape-diverse fragment set: design, synthesis and screen against aurora-A kinase, Chem A Eur J, 25, 6831, 10.1002/chem.201900815 Sveiczer, 2019, Spirocycles as rigidified sp3-rich scaffolds for a fragment collection, Org Lett, 21, 4600, 10.1021/acs.orglett.9b01499 King, 2019, Cycloaddition strategies for the synthesis of diverse heterocyclic spirocycles for fragment-based drug discovery, Eur J Org Chem, 2019, 5219, 10.1002/ejoc.201900847 Troelsen, 2020, The 3F library: fluorinated Fsp3-rich fragments for expeditious 19F NMR based screening, Angew Chem Int Ed, 59, 2204, 10.1002/anie.201913125 Hanby, 2020, Fsp3-rich and diverse fragments inspired by natural products as a collection to enhance fragment-based drug discovery, Chem Commun, 56, 2280, 10.1039/C9CC09796A Cox, 2020, Escaping from flatland: substituted bridged pyrrolidine fragments with inherent three-dimensional character, ACS Med Chem Lett, 11, 1185, 10.1021/acsmedchemlett.0c00039 Pandey, 2020, Efficient synthesis of 1,4-thiazepanones and 1,4-thiazepanes as 3D fragments for screening libraries, Org Lett, 22, 3946, 10.1021/acs.orglett.0c01230 Kidd, 2020, Demonstration of the utility of DOS-derived fragment libraries for rapid hit derivatisation in a multidirectional fashion, Chem Sci, 11, 10792, 10.1039/D0SC01232G Köster, 2011, A small nonrule of 3 compatible fragment library provides high hit rate of endothiapepsin crystal structures with various fragment chemotypes, J Med Chem, 54, 7784, 10.1021/jm200642w Colclough, 2008, High throughput solubility determination with application to selection of compounds for fragment screening, Bioorg Med Chem, 16, 6611, 10.1016/j.bmc.2008.05.021 Ramsden, 2020, Is it time for biocatalysis in fragment-based drug discovery?, Chem Sci, 11, 11104, 10.1039/D0SC04103C