Perspective pubs.acs.org/jmc
Fragment-to-Lead Medicinal Chemistry Publications in 2015 Miniperspective Christopher N. Johnson,*,† Daniel A. Erlanson,‡ Christopher W. Murray,† and David C. Rees† †
Astex Pharmaceuticals, 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, United Kingdom Carmot Therapeutics Inc., 409 Illinois Street, San Francisco, California 94158, United States
‡
ABSTRACT: Fragment-based drug discovery (FBDD) is now well-established as a technology for generating new chemical leads and drugs. This Miniperspective provides a tabulated overview of the fragment-to-lead literature published in the year 2015, together with a commentary on trends observed across the FBDD field during this time. It is hoped that this tabulated summary will provide a useful point of reference for both FBDD practitioners and the wider medicinal chemistry community. starting point has been identified by a bona fide FBDD approach; (ii) the subsequent optimization results in a meaningful increase in affinity, reaching a level appropriate for an early lead. Specifically the selection criteria employed are the following: • Fragment hit has molecular weight of 100 because it is implausible that the potency of the fragment starting point was better than low micromolar. eSurrogate crystal system used.
lead activity threshold and/or fold change criterion, particularly for challenging biological targets. The field of FBDD has been reviewed previously on many occasions,1,5,6 but this Miniperspective is the first to provide a one-year snapshot focusing exclusively on fragment to lead campaigns. Arguably the field has now reached sufficient maturity to generate enough such examples for a meaningful analysis of trends year-on-year; hence there is the potential to provide similar such snapshots on an annual basis, if warranted by interest from the wider medicinal chemistry community. It is clear that FBDD has appeal in both academia and industry (Figure 1A) across multiple organizations with a wide geographical spread. Twenty-three separate organizations are represented, with industry contributions making up two-thirds of the total and with no single institution contributing more than four examples. An important consideration for FBDD is target class applicability. The targets prosecuted successfully in 2015 (Figure 1B) range from kinases and other enzymes, through protein−protein interactions (PPIs) to a G-protein-coupled receptor. Kinase inhibitor F2L examples constitute the biggest single target class, and soluble protein targets predominate, with representation from a single example of a membranebound target. The analysis indicates that successful F2L chemistry is highly reliant on the use of X-ray crystal structures
(Figure 1C), and the challenge of obtaining such structures for membrane-bound proteins may explain the large preponderance of examples involving soluble protein targets. As X-ray crystallographic techniques for membrane-bound proteins continue to develop, it will be interesting to see whether this balance changes over time. We also analyzed the choice of screening technique(s) for each example (Figure 1D and Table 1) and found that a high concentration biochemical assay was the sole screening approach for seven examples. In general, our analysis supports the view that biochemical screening is a viable technique for tractable targets where relatively high affinity starting fragments can be identified. In contrast, examples where screens were carried out using X-ray and/or NMR gave hits with a range of affinities, with the weakest being close to 10 mM. At one time, such weakly interacting ligands would have lacked credibility as starting points for medicinal chemistry, but the examples here emphatically demonstrate the usefulness of such weak ligands for successful F2L optimization (e.g., see Table 1, entries 11 and 26). For targets of low chemical tractability such as PPIs, where fragment hits are likely to have very weak affinity, high sensitivity techniques such as X-ray and NMR should give a greater probability of hit detection. Surprisingly, surface plasmon resonance (SPR) features as a primary screening method in only 3% of the examples, despite this technique F
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Figure 1. Analysis of 27 fragment-to-lead examples with publication year 2015 showing distributions according to (A) academic, industrial, or collaborating institutions; (B) protein target class; (C) use of X-ray structural data; (D) primary screening technique (where multiple screening techniques are used in an example, each individual screen is counted separately; “none” implies knowledge-based fragment selection, i.e., extraction from literature or deconstruction of an existing ligand).
appearing among the most commonly utilized screening approaches in polls conducted on the Practical Fragments Web site; hence it will be interesting to monitor this percentage in subsequent years. The usefulness of both X-ray and biophysical techniques (such as those included in Figure 1D) as screening techniques in FBDD is underlined by the fact that at least one of these methods is used in more than half of the examples. An advantage of FBDD is that it potentially offers ligandefficient starting points for the medicinal chemist and an opportunity to control physicochemical properties during subsequent elaboration. It is therefore relevant to analyze the distribution of such properties across the 27 examples listed here. The plot of fragment hits by molecular weight (Figure 2A) shows an unequal distribution with a maximum around molecular weight 201−250 corresponding to approximately 15−18 heavy atoms. The shape of the molecular weight distribution of leads is somewhat similar to that of fragment hits (with an obvious rightward shift of approximately 200), though it is difficult to draw conclusions since this parameter is highly dependent on when researchers choose to publish, a factor that is likely to vary considerably between different institutions. Lipophilicity for fragments also follows a bell-shaped distribution (Figure 2B), again similar to that observed for molecular weight. The rightward shift in cLogP for leads compared to fragment hits is significant (approximately +2 units) and fully consistent with anecdotal observations that lipophilicity tends to increase during optimization. Ligand efficiency distribution, by contrast, appears quite similar for
fragments and leads (Figure 2C), although care should be taken in interpreting this. The set is biased toward successful F2L campaigns in that researchers will tend to publish successful examples, and the examples in Table 1 have been further curated to only include those that fit predefined progression criteria. As expected, there are definite class effects, with kinases tending to have more ligand-efficient fragments and leads than more difficult targets such as PPIs (Figure 2D). FBDD has developed to the extent that the number of published successful F2L campaigns (as defined above) in a single year is sufficient to allow some analysis and establish a baseline against which trends can be measured in subsequent years. FBDD has proved capable of tackling difficult targets, and several targets in the present analysis fall into this category. The importance of structural information for FBDD is apparent from this analysis, so lack of a protein structure has the potential to render a target off-limits. The presence of a membrane protein example (entry 27) is encouraging, showing the boundaries of FBDD are being extended, and it will be exciting to monitor the impact of techniques such as cryoelectron microscopy on the range of suitable targets. In conclusion, while these 27 examples represent a very small proportion of the total number of published medicinal chemistry optimizations reported in 2015, the number represents a significant advance on the situation at the time of previous reviews5,6 and it will be interesting to see whether this proportion continues to increase in future. G
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Figure 2. Analysis of 27 fragment-to-lead examples with publication year 2015 showing distributions according to (A) molecular weight; (B) lipophilicity (cLogP); (C) ligand efficiency. Statistical analysis using a paired sample t test shows that the differences between fragments and corresponding leads are significant for molecular weight (p ≪ 0.001) and cLogP (p ≪ 0.001) but not for ligand efficiency (p = 0.08). For the ligand efficiency analysis, only pairs where both the fragment and lead had unambiguously defined potencies were used (n = 19). (D) Plot of pKd or pIC50 versus molecular weight for fragment hits and lead molecules showing trajectory from fragment to lead; ligand efficiency of 0.3 kcal mol−1 (heavy atom)−1 is shown as a dashed line passing through the origin (assuming that a 500 Da molecule with 10 nM affinity has LE = 0.3). Examples are classified by target class as in Table 1. Note that examples without absolute numerical values are omitted from the analyses for (C) and (D).
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AUTHOR INFORMATION
Christopher W. Murray received his B.A. (1986) in chemistry and Ph.D. in theoretical chemistry (1989) from the University of Cambridge. Currently he is Senior VP of Discovery Technology at Astex, where he has contributed to the design and exploitation of fragment libraries. He has extensive experience in structure-based drug design and has helped discover a number of compounds that have demonstrated efficacy in human clinical trials.
Corresponding Author
*Phone: +44 1223 226247. Fax: +44 1223 226201. E-mail:
[email protected]. Notes
The authors declare no competing financial interest. Biographies
David C. Rees joined Astex in 2003 and is SVP Chemistry. Previously, with colleagues at Organon, he discovered sugammadex (Bridion), an anesthetic reversal agent used in over 40 countries. He is a Trustee of the Royal Society of Chemistry, is a Visiting Professor in Cancer Medicinal Chemistry at Newcastle University, and has over 100 patents and publications.
Christopher N. Johnson obtained an M.A. degree at the University of Cambridge and a Ph.D. at the University of Bristol, U.K. Following a number of years working as a medicinal chemist at GSK and legacy companies, he moved to Astex in 2008, where he has worked on fragment based approaches applied to multiple target classes including PPI antagonists, with particular focus on the oncology disease area. Dr. Johnson is a co-inventor or co-author on over 100 patents and scientific publications.
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ACKNOWLEDGMENTS
The authors are grateful to Dr. Paul Mortenson for carrying out statistical analysis and to Dr. Teddy Zartler for highlighting several of the examples discussed here on Practical Fragments.
Daniel A. Erlanson is a cofounder of Carmot Therapeutics, Inc. Prior to Carmot, Dr. Erlanson spent a decade developing technologies and leading medicinal chemistry efforts at Sunesis Pharmaceuticals, which he joined at the company’s inception. Before Sunesis, he was an NIH postdoctoral fellow with James A. Wells at Genentech. Dr. Erlanson earned his Ph.D. in chemistry from Harvard University in the laboratory of Gregory L. Verdine and his B.A. in chemistry from Carleton College. As well as coediting two books on fragment-based drug discovery, Dr. Erlanson is editor of Practical Fragments (http:// practicalfragments.blogspot.com/).
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ABBREVIATIONS USED BRAF, serine/threonine-protein kinase B-raf (raf, rapidly accelerated fibrosarcoma); Bcl-2, B-cell lymphoma 2; F2L, fragment-to-lead; LLE, ligand-lipophilicity efficiency; LLEAT, Astex ligand-lipophilicity efficiency; BTK, Bruton’s tyrosine kinase; DDR, discoidin domain-containing receptor; Tm, H
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“rule of three” for fragment-based drug discovery: where are we now? Nat. Rev. Drug Discovery 2013, 12 (8), 644−645. (8) (a) Clark, P. G.; Vieira, L. C.; Tallant, C.; Fedorov, O.; Singleton, D. C.; Rogers, C. M.; Monteiro, O. P.; Bennett, J. M.; Baronio, R.; Muller, S.; Daniels, D. L.; Mendez, J.; Knapp, S.; Brennan, P. E.; Dixon, D. J. LP99: Discovery and synthesis of the first selective BRD7/ 9 bromodomain inhibitor. Angew. Chem., Int. Ed. 2015, 54 (21), 6217− 6221. (b) Jamali, H.; Khan, H. A.; Stringer, J. R.; Chowdhury, S.; Ellman, J. A. Identification of multiple structurally distinct, nonpeptidic small molecule inhibitors of protein arginine deiminase 3 using a substrate-based fragment method. J. Am. Chem. Soc. 2015, 137 (10), 3616−3621. (c) Karpov, A. S.; Amiri, P.; Bellamacina, C.; Bellance, M. H.; Breitenstein, W.; Daniel, D.; Denay, R.; Fabbro, D.; Fernandez, C.; Galuba, I.; Guerro-Lagasse, S.; Gutmann, S.; Hinh, L.; Jahnke, W.; Klopp, J.; Lai, A.; Lindvall, M. K.; Ma, S.; Mobitz, H.; Pecchi, S.; Rummel, G.; Shoemaker, K.; Trappe, J.; Voliva, C.; Cowan-Jacob, S. W.; Marzinzik, A. L. Optimization of a dibenzodiazepine hit to a potent and selective allosteric PAK1 inhibitor. ACS Med. Chem. Lett. 2015, 6 (7), 776−781. (d) Perfetti, M. T.; Baughman, B. M.; Dickson, B. M.; Mu, Y.; Cui, G.; Mader, P.; Dong, A.; Norris, J. L.; Rothbart, S. B.; Strahl, B. D.; Brown, P. J.; Janzen, W. P.; Arrowsmith, C. H.; Mer, G.; McBride, K. M.; James, L. I.; Frye, S. V. Identification of a fragment-like small molecule ligand for the methyl-lysine binding protein, 53BP1. ACS Chem. Biol. 2015, 10 (4), 1072−1081. (e) Ranganathan, A.; Stoddart, L. A.; Hill, S. J.; Carlsson, J. Fragment-based discovery of subtype-selective adenosine receptor ligands from homology models. J. Med. Chem. 2015, 58 (24), 9578− 9590. (9) Leo, A.; Weininger, D. CLOGP reference manual, Daylight version 4.9. http://www.daylight.com/dayhtml/doc/clogp/. (10) Smith, C. R.; Dougan, D. R.; Komandla, M.; Kanouni, T.; Knight, B.; Lawson, J. D.; Sabat, M.; Taylor, E. R.; Vu, P.; Wyrick, C. Fragment-based discovery of a small molecule inhibitor of Bruton’s tyrosine kinase. J. Med. Chem. 2015, 58 (14), 5437−5444. (11) Murray, C. W.; Berdini, V.; Buck, I. M.; Carr, M. E.; Cleasby, A.; Coyle, J. E.; Curry, J. E.; Day, J. E.; Day, P. J.; Hearn, K.; Iqbal, A.; Lee, L. Y.; Martins, V.; Mortenson, P. N.; Munck, J. M.; Page, L. W.; Patel, S.; Roomans, S.; Smith, K.; Tamanini, E.; Saxty, G. Fragment-based discovery of potent and selective DDR1/2 Inhibitors. ACS Med. Chem. Lett. 2015, 6 (7), 798−803. (12) Burdick, D. J.; Wang, S.; Heise, C.; Pan, B.; Drummond, J.; Yin, J.; Goeser, L.; Magnuson, S.; Blaney, J.; Moffat, J.; Wang, W.; Chen, H. Fragment-based discovery of potent ERK2 pyrrolopyrazine inhibitors. Bioorg. Med. Chem. Lett. 2015, 25 (21), 4728−4732. (13) Johnson, C. N.; Berdini, V.; Beke, L.; Bonnet, P.; Brehmer, D.; Coyle, J. E.; Day, P. J.; Frederickson, M.; Freyne, E. J.; Gilissen, R. A.; Hamlett, C. C.; Howard, S.; Meerpoel, L.; McMenamin, R.; Patel, S.; Rees, D. C.; Sharff, A.; Sommen, F.; Wu, T.; Linders, J. T. Fragmentbased discovery of type I inhibitors of maternal embryonic leucine zipper kinase. ACS Med. Chem. Lett. 2015, 6 (1), 25−30. (14) Johnson, C. N.; Adelinet, C.; Berdini, V.; Beke, L.; Bonnet, P.; Brehmer, D.; Calo, F.; Coyle, J. E.; Day, P. J.; Frederickson, M.; Freyne, E. J.; Gilissen, R. A.; Hamlett, C. C.; Howard, S.; Meerpoel, L.; Mevellec, L.; McMenamin, R.; Pasquier, E.; Patel, S.; Rees, D. C.; Linders, J. T. Structure-based design of type II inhibitors applied to maternal embryonic leucine zipper kinase. ACS Med. Chem. Lett. 2015, 6 (1), 31−36. (15) Naik, M.; Raichurkar, A.; Bandodkar, B. S.; Varun, B. V.; Bhat, S.; Kalkhambkar, R.; Murugan, K.; Menon, R.; Bhat, J.; Paul, B.; Iyer, H.; Hussein, S.; Tucker, J. A.; Vogtherr, M.; Embrey, K. J.; McMiken, H.; Prasad, S.; Gill, A.; Ugarkar, B. G.; Venkatraman, J.; Read, J.; Panda, M. Structure guided lead generation for M. tuberculosis thymidylate kinase (Mtb TMK): discovery of 3-cyanopyridone and 1,6-naphthyridin-2-one as potent inhibitors. J. Med. Chem. 2015, 58 (2), 753−766. (16) Hu, H.; Wang, X.; Chan, G. K.; Chang, J. H.; Do, S.; Drummond, J.; Ebens, A.; Lee, W.; Ly, J.; Lyssikatos, J. P.; Murray, J.; Moffat, J. G.; Chao, Q.; Tsui, V.; Wallweber, H.; Kolesnikov, A.
melting temperature (of a protein); ERK2, extracellular signalregulated kinase 2; MELK, maternal embryonic leucine zipper kinase; Mtb TMK, Mycobacterium tuberculosis thymidylate kinase; Pim-2, proviral integrations of Moloney virus 2; PKCθ, protein kinase C θ type; RET, rearranged during transfection; VEGFR2, vascular endothelial growth factor receptor 2; MMP-13, matrix metalloproteinase 13 (or collagenase 3); BCATm, branched-chain amino acid aminotransferase, mitochondrial; mPTPB, mycobacterium phosphotyrosine protein phosphatase; UBLCP1, ubiquitin-like domaincontaining CTD phosphatase 1; ATAD2, ATPase family AAA domain-containing protein 2; BET, bromodomain and extraterminal domain family member; Mcl-1, induced myeloid leukemia cell differentiation protein; PPI, protein−protein interaction; RPA, replication protein A; XIAP, X-linked inhibitor of apoptosis protein; cIAP, cellular inhibitor of apoptosis protein; mGluR5, metabotropic glutamate receptor 5; SPR, surface plasmon resonance
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REFERENCES
(1) (a) Davis, B. J.; Erlanson, D. A. Learning from our mistakes: the “unknown knowns” in fragment screening. Bioorg. Med. Chem. Lett. 2013, 23 (10), 2844−2852. (b) Erlanson, D. A. Introduction to fragment-based drug discovery. Top. Curr. Chem. 2011, 317, 1−32. (c) Erlanson, D. A.; Fesik, S. W.; Hubbard, R. E.; Jahnke, W.; Jhoti, H. Twenty years on: the impact of fragments on drug discovery. Nat. Rev. Drug Discovery 2016, 15 (9), 605−619. (d) Hubbard, R. E.; Murray, J. B. Experiences in fragment-based lead discovery. Methods Enzymol. 2011, 493, 509−531. (e) Magee, T. V. Progress in discovery of smallmolecule modulators of protein-protein interactions via fragment screening. Bioorg. Med. Chem. Lett. 2015, 25, 2461−2468. (f) Murray, C. W.; Rees, D. C. The rise of fragment-based drug discovery. Nat. Chem. 2009, 1, 187−192. (g) Zartler, E. R. Fragonomics: the -omics with real impact. ACS Med. Chem. Lett. 2014, 5 (9), 952−953. (2) Baker, M. Fragment-based lead discovery grows up. Nat. Rev. Drug Discovery 2013, 12 (1), 5−7. (3) Bollag, G.; Tsai, J.; Zhang, J.; Zhang, C.; Ibrahim, P.; Nolop, K.; Hirth, P. Vemurafenib: the first drug approved for BRAF-mutant cancer. Nat. Rev. Drug Discovery 2012, 11 (11), 873−886. (4) Souers, A. J.; Leverson, J. D.; Boghaert, E. R.; Ackler, S. L.; Catron, N. D.; Chen, J.; Dayton, B. D.; Ding, H.; Enschede, S. H.; Fairbrother, W. J.; Huang, D. C.; Hymowitz, S. G.; Jin, S.; Khaw, S. L.; Kovar, P. J.; Lam, L. T.; Lee, J.; Maecker, H. L.; Marsh, K. C.; Mason, K. D.; Mitten, M. J.; Nimmer, P. M.; Oleksijew, A.; Park, C. H.; Park, C. M.; Phillips, D. C.; Roberts, A. W.; Sampath, D.; Seymour, J. F.; Smith, M. L.; Sullivan, G. M.; Tahir, S. K.; Tse, C.; Wendt, M. D.; Xiao, Y.; Xue, J. C.; Zhang, H.; Humerickhouse, R. A.; Rosenberg, S. H.; Elmore, S. W. ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat. Med. 2013, 19 (2), 202−208. (5) (a) Alex, A. A.; Flocco, M. M. Fragment-based drug discovery: what has it achieved so far? Curr. Top. Med. Chem. 2007, 7 (16), 1544−1567. (b) Congreve, M.; Murray, C. W.; Carr, R.; Rees, D. C. Fragment-based lead discovery. In Annual Reports in Medicinal Chemistry; John, E. M., Ed.; Academic Press: New York, NY, 2007; Vol. 42, Chapter 28, pp 431−448. (c) de Kloe, G. E.; Bailey, D.; Leurs, R.; de Esch, I. J. Transforming fragments into candidates: small becomes big in medicinal chemistry. Drug Discovery Today 2009, 14 (13−14), 630−646. (d) Erlanson, D. A. Fragment-based lead discovery: a chemical update. Curr. Opin. Biotechnol. 2006, 17 (6), 643−652. (6) Ferenczy, G. G.; Keseru, G. M. How are fragments optimized? A retrospective analysis of 145 fragment optimizations. J. Med. Chem. 2013, 56 (6), 2478−2486. (7) (a) Congreve, M.; Carr, R.; Murray, C.; Jhoti, H. A “rule of three” for fragment-based lead discovery? Drug Discovery Today 2003, 8 (19), 876−877. (b) Jhoti, H.; Williams, G.; Rees, D. C.; Murray, C. W. The I
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Perspective
Discovery of 3,5-substituted 6-azaindazoles as potent pan-Pim inhibitors. Bioorg. Med. Chem. Lett. 2015, 25 (22), 5258−5264. (17) George, D. M.; Breinlinger, E. C.; Friedman, M.; Zhang, Y.; Wang, J.; Argiriadi, M.; Bansal-Pakala, P.; Barth, M.; Duignan, D. B.; Honore, P.; Lang, Q.; Mittelstadt, S.; Potin, D.; Rundell, L.; Edmunds, J. J. Discovery of selective and orally bioavailable protein kinase Ctheta (PKCtheta) inhibitors from a fragment hit. J. Med. Chem. 2015, 58 (1), 222−236. (18) Frett, B.; Carlomagno, F.; Moccia, M. L.; Brescia, A.; Federico, G.; De Falco, V.; Admire, B.; Chen, Z.; Qi, W.; Santoro, M.; Li, H. Y. Fragment-based discovery of a dual pan-RET/VEGFR2 kinase inhibitor optimized for single-agent polypharmacology. Angew. Chem., Int. Ed. 2015, 54 (30), 8717−8721. (19) Winneroski, L. L.; Schiffler, M. A.; Erickson, J. A.; May, P. C.; Monk, S. A.; Timm, D. E.; Audia, J. E.; Beck, J. P.; Boggs, L. N.; Borders, A. R.; Boyer, R. D.; Brier, R. A.; Hudziak, K. J.; Klimkowski, V. J.; Garcia Losada, P.; Mathes, B. M.; Stout, S. L.; Watson, B. M.; Mergott, D. J. Preparation and biological evaluation of conformationally constrained BACE1 inhibitors. Bioorg. Med. Chem. 2015, 23 (13), 3260−3268. (20) Cheney, D. L.; Bozarth, J. M.; Metzler, W. J.; Morin, P. E.; Mueller, L.; Newitt, J. A.; Nirschl, A. H.; Rendina, A. R.; Tamura, J. K.; Wei, A.; Wen, X.; Wurtz, N. R.; Seiffert, D. A.; Wexler, R. R.; Priestley, E. S. Discovery of novel P1 groups for coagulation factor VIIa inhibition using fragment-based screening. J. Med. Chem. 2015, 58 (6), 2799−2808. (21) Fjellstrom, O.; Akkaya, S.; Beisel, H. G.; Eriksson, P. O.; Erixon, K.; Gustafsson, D.; Jurva, U.; Kang, D.; Karis, D.; Knecht, W.; Nerme, V.; Nilsson, I.; Olsson, T.; Redzic, A.; Roth, R.; Sandmark, J.; Tigerstrom, A.; Oster, L. Creating novel activated factor XI inhibitors through fragment based lead generation and structure aided drug design. PLoS One 2015, 10 (1), e0113705. (22) Lanz, J.; Riedl, R. Merging allosteric and active site binding motifs: de novo generation of target selectivity and potency via natural-product-derived fragments. ChemMedChem 2015, 10 (3), 451−454. (23) Bertrand, S. M.; Ancellin, N.; Beaufils, B.; Bingham, R. P.; Borthwick, J. A.; Boullay, A. B.; Boursier, E.; Carter, P. S.; Chung, C. W.; Churcher, I.; Dodic, N.; Fouchet, M. H.; Fournier, C.; Francis, P. L.; Gummer, L. A.; Herry, K.; Hobbs, A.; Hobbs, C. I.; Homes, P.; Jamieson, C.; Nicodeme, E.; Pickett, S. D.; Reid, I. H.; Simpson, G. L.; Sloan, L. A.; Smith, S. E.; Somers, D. O.; Spitzfaden, C.; Suckling, C. J.; Valko, K.; Washio, Y.; Young, R. J. The discovery of in vivo active mitochondrial branched-chain aminotransferase (BCATm) inhibitors by hybridizing fragment and HTS hits. J. Med. Chem. 2015, 58 (18), 7140−7163. (24) Chen, G.-Y.; Ng, F. M.; Tan, Y. W.; Poulsen, A.; Seetoh, W.; Lin, G.; Kang, C.; Then, S. W.; Ahmad, N. H.; Wong, Y. L.; Ng, H. Q.; Chia, C. S. B.; Lau, Q. Y.; Hill, J.; Hung, A. W.; Keller, T. H. Application of fragment-based drug discovery against DNA gyrase B. ChemPlusChem 2015, 80 (8), 1250−1254. (25) Hale, M. R.; Brassington, C.; Carcanague, D.; Embrey, K.; Eyermann, C. J.; Giacobbe, R. A.; Gingipalli, L.; Gowravaram, M.; Harang, J.; Howard, T.; Ioannidis, G.; Jahic, H.; Kutschke, A.; Laganas, V. A.; Loch, J.; Miller, M. D.; Murphy-Benenato, K. E.; Oguto, H.; Otterbein, L.; Patel, S. J.; Shapiro, A. B.; Boriack-Sjodin, P. A. From fragments to leads: novel bacterial NAD+-dependent DNA ligase inhibitors. Tetrahedron Lett. 2015, 56 (23), 3108−3112. (26) He, R.; Yu, Z. H.; Zhang, R. Y.; Wu, L.; Gunawan, A. M.; Zhang, Z. Y. Cefsulodin inspired potent and selective inhibitors of mPTPB, a virulent phosphatase from mycobacterium tuberculosis. ACS Med. Chem. Lett. 2015, 6 (12), 1231−1235. (27) Shipe, W. D.; Sharik, S. S.; Barrow, J. C.; McGaughey, G. B.; Theberge, C. R.; Uslaner, J. M.; Yan, Y.; Renger, J. J.; Smith, S. M.; Coleman, P. J.; Cox, C. D. Discovery and optimization of a series of pyrimidine-based phosphodiesterase 10A (PDE10A) inhibitors through fragment screening, structure-based design, and parallel synthesis. J. Med. Chem. 2015, 58 (19), 7888−7894.
(28) Amano, Y.; Tanabe, E.; Yamaguchi, T. Identification of Nethylmethylamine as a novel scaffold for inhibitors of soluble epoxide hydrolase by crystallographic fragment screening. Bioorg. Med. Chem. 2015, 23 (10), 2310−2317. (29) de Vicente, J.; Tivitmahaisoon, P.; Berry, P.; Bolin, D. R.; Carvajal, D.; He, W.; Huang, K. S.; Janson, C.; Liang, L.; Lukacs, C.; Petersen, A.; Qian, H.; Yi, L.; Zhuang, Y.; Hermann, J. C. Fragmentbased drug design of novel pyranopyridones as cell active and orally bioavailable tankyrase inhibitors. ACS Med. Chem. Lett. 2015, 6 (9), 1019−1024. (30) He, Y.; Guo, X.; Yu, Z. H.; Wu, L.; Gunawan, A. M.; Zhang, Y.; Dixon, J. E.; Zhang, Z. Y. A potent and selective inhibitor for the UBLCP1 proteasome phosphatase. Bioorg. Med. Chem. 2015, 23 (12), 2798−2809. (31) (a) Bamborough, P.; Chung, C. W.; Furze, R. C.; Grandi, P.; Michon, A. M.; Sheppard, R. J.; Barnett, H.; Diallo, H.; Dixon, D. P.; Douault, C.; Jones, E. J.; Karamshi, B.; Mitchell, D. J.; Prinjha, R. K.; Rau, C.; Watson, R. J.; Werner, T.; Demont, E. H. Structure-based optimization of naphthyridones into potent ATAD2 bromodomain inhibitors. J. Med. Chem. 2015, 58 (15), 6151−6178. (b) Demont, E. H.; Chung, C. W.; Furze, R. C.; Grandi, P.; Michon, A. M.; Wellaway, C.; Barrett, N.; Bridges, A. M.; Craggs, P. D.; Diallo, H.; Dixon, D. P.; Douault, C.; Emmons, A. J.; Jones, E. J.; Karamshi, B. V.; Locke, K.; Mitchell, D. J.; Mouzon, B. H.; Prinjha, R. K.; Roberts, A. D.; Sheppard, R. J.; Watson, R. J.; Bamborough, P. Fragment-based discovery of low-micromolar ATAD2 bromodomain inhibitors. J. Med. Chem. 2015, 58 (14), 5649−5673. (32) Burke, J. P.; Bian, Z.; Shaw, S.; Zhao, B.; Goodwin, C. M.; Belmar, J.; Browning, C. F.; Vigil, D.; Friberg, A.; Camper, D. V.; Rossanese, O. W.; Lee, T.; Olejniczak, E. T.; Fesik, S. W. Discovery of tricyclic indoles that potently inhibit Mcl-1 using fragment-based methods and structure-based design. J. Med. Chem. 2015, 58 (9), 3794−3805. (33) Scott, D. E.; Coyne, A. G.; Venkitaraman, A.; Blundell, T. L.; Abell, C.; Hyvonen, M. Small-molecule inhibitors that target proteinprotein interactions in the RAD51 family of recombinases. ChemMedChem 2015, 10 (2), 296−303. (34) Waterson, A. G.; Kennedy, J. P.; Patrone, J. D.; Pelz, N. F.; Feldkamp, M. D.; Frank, A. O.; Vangamudi, B.; Souza-Fagundes, E. M.; Rossanese, O. W.; Chazin, W. J.; Fesik, S. W. Diphenylpyrazoles as replication protein a inhibitors. ACS Med. Chem. Lett. 2015, 6 (2), 140−145. (35) Chessari, G.; Buck, I. M.; Day, J. E.; Day, P. J.; Iqbal, A.; Johnson, C. N.; Lewis, E. J.; Martins, V.; Miller, D.; Reader, M.; Rees, D. C.; Rich, S. J.; Tamanini, E.; Vitorino, M.; Ward, G. A.; Williams, P. A.; Williams, G.; Wilsher, N. E.; Woolford, A. J. Fragment-based drug discovery targeting inhibitor of apoptosis proteins: discovery of a nonalanine lead series with dual activity against cIAP1 and XIAP. J. Med. Chem. 2015, 58 (16), 6574−6588. (36) Christopher, J. A.; Aves, S. J.; Bennett, K. A.; Dore, A. S.; Errey, J. C.; Jazayeri, A.; Marshall, F. H.; Okrasa, K.; Serrano-Vega, M. J.; Tehan, B. G.; Wiggin, G. R.; Congreve, M. Fragment and structurebased drug discovery for a class C GPCR: discovery of the mGlu5 negative allosteric modulator HTL14242 (3-Chloro-5-[6-(5-fluoropyridin-2-yl)pyrimidin-4-yl]benzonitrile). J. Med. Chem. 2015, 58 (16), 6653−6664. (37) Hopkins, A. L.; Groom, C. R.; Alex, A. Ligand efficiency: a useful metric for lead selection. Drug Discovery Today 2004, 9 (10), 430−431. (38) Leeson, P. D.; Springthorpe, B. The influence of drug-like concepts on decision-making in medicinal chemistry. Nat. Rev. Drug Discovery 2007, 6 (11), 881−890. (39) Ryckmans, T.; Edwards, M. P.; Horne, V. A.; Correia, A. M.; Owen, D. R.; Thompson, L. R.; Tran, I.; Tutt, M. F.; Young, T. Rapid assessment of a novel series of selective CB(2) agonists using parallel synthesis protocols: a lipophilic efficiency (LipE) analysis. Bioorg. Med. Chem. Lett. 2009, 19 (15), 4406−4409. J
DOI: 10.1021/acs.jmedchem.6b01123 J. Med. Chem. XXXX, XXX, XXX−XXX
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(40) Mortenson, P. N.; Murray, C. W. Assessing the lipophilicity of fragments and early hits. J. Comput.-Aided Mol. Des. 2011, 25 (7), 663−667.
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