Recent Publications - Center for Integrative Chemical Biology and Drug Discovery

Devan J. Shell, Caroline A. Foley, Qinhong Wang, Chelsea M. Smith, Shiva K. R. Guduru, Hong Zeng, Aiping Dong, Jacqueline L. Norris-Drouin, Matthew Axtman, P. Brian Hardy, Gaorav Gupta, Levon Halabelian, Stephen V. Frye, Lindsey I. James, and Kenneth H. Pearce Discovery of a 53BP1 Small Molecule Antagonist Using a Focused DNA-Encoded Library Screen J. Med. Chem. Publication Date:October 2, 2023
Ottavi S., Scarry S.M., Mosior J., Ling Y., Roberts J., Singh A., Zhang D., Goullieux L., Roubert C., Bacqué E., Lagiakos H.R., Vendome J. In Vitro and in Vivo Inhibition of the Mycobacterium tuberculosis Phosphopantetheinyl Transferase PptT by Amidinoureas (2021). Journal of Medicinal Chemistry.
Kean K.M., Baril S.A., Lamb K.N., Dishman S.N., Treacy J.W., Houk K.N., Brustad E.M., James L.I., Waters M.L. Systematic Variation of Both the Aromatic Cage and Dialkyllysine via GCE-SAR Reveal Mechanistic Insights in CBX5 Reader Protein Binding (2021). Journal of Medicinal Chemistry.
Zeller M.J., Nuthanakanti A., Li K., Aubé J., Serganov A., Weeks K.M. Subsite Ligand Recognition and Cooperativity in the TPP Riboswitch: Implications for Fragment-Linking in RNA Ligand Discovery (2021). ACS Chemical Biology.
Sun Z.-W., Waybright J.M., Beldar S., Chen L., Foley C.A., Norris-Drouin J.L., Lyu T.-J., Dong A., Min J., Wang Y.-P., James L.I., Wang Y. Cdyl Deficiency Brakes Neuronal Excitability and Nociception through Promoting Kcnb1 Transcription in Peripheral Sensory Neurons (2022). Advanced Science.
Dilworth D, Hanley RP, Ferreira de Freitas R, Allali-Hassani A, Zhou M, Mehta N, Marunde MR, Ackloo S, Carvalho Machado RA, Khalili Yazdi A, Owens DDG, Vu V, Nie DY, Alqazzaz M, Marcon E, Li F, Chau I, Bolotokova A, Qin S, Lei M, Liu Y, Szewczyk MM, Dong A, Kazemzadeh S, Abramyan T, Popova IK, Hall NW, Meiners MJ, Cheek MA, Gibson E, Kireev D, Greenblatt JF, Keogh MC, Min J, Brown PJ, Vedadi M, Arrowsmith CH, Barsyte-Lovejoy D, James LI, Schapira M. A chemical probe targeting the PWWP domain alters NSD2 nucleolar localization Nat Chem Biol. 2021 Nov 15. doi: 10.1038/s41589-021-00898-0. Online ahead of print. PMID: 34782742
Zheng, H.; Zhao, J.; Li, B.; Zhang, W.; Stashko, M. A.; Minson, K. A.; Huey, M. G.; Earp, H. S.; Kireev, D. B.; Graham, D. K.; DeRyckere, D.; Frye, S. V.; Wang, X.* UNC5293, a Potent, Orally Available and Highly MERTK-selective Inhibitor. Eur. J. Med. Chem. 2021, 220, 113534
Engelberg, I. A.; Liu, J.; Norris-Drouin, J. L.; Cholensky, S. H.; Ottavi, S. A.; Frye, S. V.; Kutateladze, T. G.; James, L. I., Discovery of an H3K36me3-Derived Peptidomimetic Ligand with Enhanced Affinity for Plant Homeodomain Finger Protein 1 (PHF1). Journal of Medicinal Chemistry 2021.
Suh, J. L.; Bsteh, D.; Si, Y.; Hart, B.; Weaver, T. M.; Pribitzer, C.; Lau, R.; Soni, S.; Ogana, H.; Rectenwald, J. M.; Norris, J. L.; Cholensky, S. H.; Sagum, C.; Umana, J. D.; Li, D.; Hardy, B.; Bedford, M. T.; Mumenthaler, S. M.; Lenz, H.-J.; Kim, Y.-m.; Wang, G. G.; Pearce, K. H.; James, L.; Kireev, D. B.; Musselman, C. A.; Frye, S. V.; Bell, O.,REPROGRAMMING CBX8-PRC1 FUNCTION WITH A POSITIVE ALLOSTERIC MODULATOR. bioRxiv 2021, 2021.02.23.432388.
Mandeep K. Mann, Ivan Franzoni, Renato Ferreira de Freitas, Wolfram Tempel, Scott Houliston, Leanna Smith, Masoud Vedadi, Cheryl H. Arrowsmith, Rachel J. Harding*, Matthieu Schapira*. Discovery of Small-Molecule Antagonists of the PWWP Domain of NSD2 J. Med. Chem. October 8, 2020
Isabelle A. Engelberg, Caroline A. Foley, Lindsey I. James and Stephen V. Frye. Improved methods for targeting epigenetic reader domains of acetylated and methylated lysine Science Direct 2021
Jason M. Rohde, Surendra Karavadhi, Rajan Pragani, Li Liu, Yuhong Fang, Weihe Zhang, Andrew McIver, Hongchao Zheng, Qingyang Liu, Mindy I. Davis, Daniel J. Urban, Tobie D. Lee, Dorian M. Cheff, Melinda Hollingshead, Mark J. Henderson, Natalia J. Martinez, Kyle R. Brimacombe, Adam Yasgar, Wei Zhao, Carleen Klumpp-Thomas, Sam Michael, Joseph Covey, William J. Moore, Gordon M. Stott, Zhuyin Li, Anton Simeonov, Ajit Jadhav, Stephen Frye, Matthew D. Hall*, Min Shen*, Xiaodong Wang*, Samarjit Patnaik*, and Matthew B. Boxer. Discovery and Optimization of 2H-1λ²-Pyridin-2-one Inhibitors of Mutant Isocitrate Dehydrogenase 1 for the Treatment of Cancer J. Med. Chem. April 6 2021
a, CD; Imamura, M; Talley, DC; Rolt, A; Xu, X; Wang, AQ; Le, D; Uchida, T; Osawa, M; Teraoka, Y; Li, K; Hu, X; Park, SB; Chalasani, N; Irvin, PH; Dulcey, AE; Southall, N; Marugan, JJ; Hu, Z; Chayama, K; Frankowski, KJ; Liang, TJ. Fluoxazolevir inhibits hepatitis C virus infection in humanized chimeric mice by blocking viral membrane fusion Nat. Microbiol. 2020
Luderman, KD; Jain, P; Free, RB; Conroy, JL; Aubé, J; Sibley, DR*; Frankowski, KF*. Development of pyrimidone D1 dopamine receptor positive allosteric modulators Bioorg. Med. Chem. Lett. 2020
Goulet DR, Foster JP 2nd, Zawistowski JS, Bevill SM, Noël MP, Olivares-Quintero JF, Sciaky N, Singh D, Santos C, Pattenden SG, Davis IJ, Johnson GL. Discrete Adaptive Responses to MEK Inhibitor in Subpopulations of Triple-Negative Breast Cancer. Mol Cancer Res. 2020 Nov
Lemke M, Ravenscroft H, Rueb NJ, Kireev D, Ferraris D, Franzini RM. Bioorg Med Chem Lett.Integrating
DNA-encoded chemical libraries with virtual combinatorial library screening: Optimizing a PARP10 inhibitor 2020 Aug 5;30(19):127464. doi: 10.1016/j.bmcl.2020.127464. Online ahead of print. PMID: 32768646
Goulet DR, Foster JP 2nd, Zawistowski JS, Bevill SM, Noël MP, Olivares-Quintero JF, Sciaky N, Singh D, Santos C, Pattenden SG, Davis IJ, Johnson GL. Discrete Adaptive Responses to MEK Inhibitor in Subpopulations of Triple-Negative Breast Cancer Mol Cancer Res. 2020 Aug 4. doi: 10.1158/1541-7786.MCR-19-1011. Online ahead of print.PMID: 32753473
Aleksandra Skrajna, Dennis Goldfarb, Katarzyna M Kedziora, Emily M Cousins, Gavin D Grant, Cathy J Spangler, Emily H Barbour, Xiaokang Yan, Nathaniel A Hathaway, Nicholas G Brown, Jeanette G Cook, Michael B Major, Robert K McGinty Comprehensive nucleosome interactome screen establishes fundamental principles of nucleosome binding 07 July 2020 Nucleic Acids Research
Puhl, A.C., Bogart, J.W., Haberman, V.A., Larson, J.E., Godoy, A.S., Norris-Drouin, J.L., Cholensky, S.H., Leisner, T.M., Frye, S.V., Parise, L.V., Bowers, A.A., Pearce, K.H. Discovery and Characterization of Peptide Inhibitors for Calcium and Integrin Binding Protein 1 92020). ACS Chemical Biology.
Su YT, Butler M, Zhang M, Zhang W, Song H, Hwang L, Tran AD, Bash RE, Schorzman AN, Pang Y, Yu G, Zamboni WC, Wang X, Frye SV, Miller CR, Maric D, Terabe M, Gilbert MR, Earp Iii HS, Wu J. MerTK inhibition decreases immune suppressive glioblastoma-associated macrophages and neoangiogenesis in glioblastoma microenvironment Neurooncol Adv. 2020 Jun 3;2(1):vdaa065. doi: 10.1093/noajnl/vdaa065. eCollection 2020 Jan-Dec. PMID: 32642716
Moritz AE, Free RB, Weiner WS, Akano EO, Gandhi D, Abramyan A, Keck TM, Ferrer M, Hu X, Southall N, Steiner J, Aubé J, Shi L, Frankowski KJ, Sibley DR. Discovery, Optimization, and Characterization of ML417: A Novel and Highly Selective D₃ Dopamine Receptor Agonist. 2020 May 12. doi: 10.1021/acs.jmedchem.0c00424. [Epub ahead of print]
Dong C, Liu Y, Lyu TJ, Beldar S, Lamb KN, Tempel W, Li Y, Li Z, James LI, Qin S, Wang Y, Min J. Structural Basis for the Binding Selectivity of Human CDY Chromodomains. Cell Chem Biol. 2020 Jul 16;27(7):827-838.e7. doi: 10.1016/j.chembiol.2020.05.007. Epub 2020 May 28. PMID: 32470319
Turner AM, Dronamraju R, Potjewyd FM, Sholtis K, Winecoff D, Kirchherr J, Archin N, Browne E, Strahl BD, Margolis D, James LI. Evaluation of EED Inhibitors as a Class of PRC2-Targeted Small Molecules for HIV Latency Reversal. 2020 Apr 29 ACS Infect Dis doi: 10.1021/acsinfecdis.9b00514. Online ahead of print.
Hu L, Xie H, Liu X, Potjewyd F, James LI, Wilkerson EM, Herring LE, Xie L, Chen X, Cabrera JC, Hong K, Liao C, Tan X, Baldwin AS, Gong K, Zhang Q. TBK1 Is a Synthetic Lethal Target in Cancer with VHL Loss Cancer Discov. 2020 Mar;10(3):460-475. doi: 10.1158/2159-8290.CD-19-0837. Epub 2019 Dec 6. PMID: 31810986
Abramyan, T.M., An, Y., Kireev, D. Off-Pocket Activity Cliffs: A Puzzling Facet of Molecular Recognition (2020). Journal of Chemical Information and Modeling, 60(1), pp. 152-161.
Chiarella, A.M., Lu, D., Hathaway, N.A. Epigenetic Control of a Local Chromatin Landscape, (2020). International journal of molecular sciences, 21(3).
Waybright JM, James LI. Getting a handle on chemical probes of chromatin readers [published online ahead of print, 2020 Jan 10]. Future Med Chem. 2020;10.4155/fmc-2019-0274. doi:10.4155/fmc-2019-0274
Rectenwald JM, Guduru SKR, Dang Z, Collins LB, Liao YE, Norris-Drouin JL, Cholensky SH, Kaufmann KW, Hammond SM, Kireev DB, Frye SV, Pearce KH. Design and Construction of a Focused DNA-Encoded Library for Multivalent Chromatin Reader Proteins. Molecules. 2020;25(4):979. Published 2020 Feb 22. doi:10.3390/molecules25040979.
Atkins SL, Motaib S, Wiser LC, Hopcraft SE, Hardy PB, Shackelford J, Foote P, Wade AH, Damania B, Pagano JS, Pearce KH, Whitehurst CB. Small molecule screening identifies inhibitors of the Epstein-Barr virus deubiquitinating enzyme, BPLF1. Antiviral Res. 2020;173:104649. doi:10.1016/j.antiviral.2019.104649
Hu L, Xie H, Liu X, Potjewyd F, James LI, Wilkerson EM, Herring LE, Xie L, Chen X, Cabrera JC, Hong K, Liao C, Tan X, Baldwin AS, Gong K, Zhang Q. TBK1 Is a Synthetic Lethal Target in Cancer with VHL Loss. Cancer Discov. 2020;10(3):460–475. doi:10.1158/2159-8290.CD-19-0837
Gu C, Stashko MA, Puhl-Rubio AC, Chakraborty M, Chakraborty A, Frye SV, Pearce KH, Wang X, Shears SB, Wang H. Inhibition of Inositol Polyphosphate Kinases by Quercetin and Related Flavonoids: A Structure-Activity Analysis. J Med Chem. 2019 Feb 14;62(3):1443-1454. doi: 10.1021/acs.jmedchem.8b01593. Epub 2019 Jan 25. PubMed PMID: 30624931; PubMed Central PMCID: PMC6467728.
Foley, C.A., Potjewyd, F., Lamb, K.N., James, L.I., Frye, S.V. Assessing the cell permeability of bivalent chemical degraders using the chloroalkane penetration assay (2020). ACS Chemical Biology, 15(1), pp. 290-295.
Potjewyd, F., Turner, A.-M.W., Beri, J., Rectenwald, J.M., Norris-Drouin, J.L., Cholensky, S.H., Margolis, D.M., Pearce, K.H., Herring, L.E., James, L.I. Degradation of Polycomb Repressive Complex 2 with an EED-Targeted Bivalent Chemical Degrader (2020). Cell Chemical Biology, 27(1), pp. 47-56.e15.
Chiarella, A.M., Butler, K.V., Gryder, B.E., Lu, D., Wang, T.A., Yu, X., Pomella, S., Khan, J., Jin, J., Hathaway, N.A. Dose-dependent activation of gene expression is achieved using CRISPR and small molecules that recruit endogenous chromatin machinery (2020). Nature Biotechnology, 38(1), pp. 50-55.
Moussa HF, Bsteh D, Yelagandula R, Pribitzer C, Stecher K, Bartalska K, Michetti L, Wang J, Zepeda-Martinez JA, Elling U, Stuckey JI, James LI, Frye SV, Bell O. Canonical PRC1 controls sequence-independent propagation of Polycomb-mediated gene silencing. Nat Commun. 2019;10(1):1931. Published 2019 Apr 29. doi:10.1038/s41467-019-09628-6
An Y, Jessen HJ, Wang H, Shears SB, Kireev D. Dynamics of Substrate Processing by PPIP5K2, a Versatile Catalytic Machine. Structure. 2019;27(6):1022–1028.e2. doi:10.1016/j.str.2019.03.007
Da C, Zhang D, Stashko M, Vasileiadi E, Parker RE, Minson KA, Huey MG, Huelse JM, Hunter D, Gilbert TSK, Norris-Drouin J, Miley M, Herring LE, Graves LM, DeRyckere D, Earp HS, Graham DK, Frye SV, Wang X, Kireev D.Data-Driven Construction of Antitumor Agents with Controlled Polypharmacology. J Am Chem Soc. 2019;141(39):15700–15709. doi:10.1021/jacs.9b08660
Lamb KN, Bsteh D, Dishman SN, Moussa HF, Fan H, Stuckey JI, Norris JL, Cholensky SH, Li D, Wang J, Sagum C, Stanton BZ, Bedford MT, Pearce KH, Kenakin TP, Kireev DB, Wang GG, James LI, Bell O, Frye SV. Discovery and Characterization of a Cellular Potent Positive Allosteric Modulator of the Polycomb Repressive Complex 1 Chromodomain, CBX7. Cell Chem Biol. 2019;26(10):1365–1379.e22. doi:10.1016/j.chembiol.2019.07.013
Gryder BE, Pomella S, Sayers C, Wu XS, Song Y, Chiarella AM, Bagchi S, Chou HC, Sinniah RS, Walton A, Wen X, Rota R, Hathaway NA, Zhao K, Chen J, Vakoc CR, Shern JF, Stanton BZ, Khan J. Histone hyperacetylation disrupts core gene regulatory architecture in rhabdomyosarcoma. Nat Genet. 2019;51(12):1714–1722. doi:10.1038/s41588-019-0534-4
Rectenwald JM, Hardy PB, Norris-Drouin JL, Cholensky SH, James LI, Frye SV, Pearce KH. A General TR-FRET Assay Platform for High-Throughput Screening and Characterizing Inhibitors of Methyl-Lysine Reader Proteins. SLAS Discov. 2019;24(6):693–700. doi:10.1177/2472555219844569
Suh JL, Barnash KD, Abramyan TM, Li F, The J, Engelberg IA, Vedadi M, Brown PJ, Kireev DB, Arrowsmith CH, James LI, Frye SV. Discovery of selective activators of PRC2 mutant EED-I363M. Sci Rep. 2019;9(1):6524. Published 2019 Apr 25. doi:10.1038/s41598-019-43005-z
Madigan VJ, Yuziuk JA, Chiarella AM, Tyson TO, Meganck RM, Elmore ZC, Tse LV, Hathaway NA, Asokan A.. Ring finger protein 121 is a potent regulator of adeno-associated viral genome transcription. PLoS Pathog.
Hu L, Xie H, Liu X, Potjewyd F, James LI, Wilkerson EM, Herring LE, Xie L, Chen X, Cabrera JC, Hong K, Liao C, Tan X, Baldwin AS, Gong K, Zhang Q. TBK1 Is a Synthetic Lethal Target in Cancer with VHL Loss. Cancer Discov. 2020;10(3):460–475. doi:10.1158/2159-8290.CD-19-0837
Pan Z, Dumas EK, Lawrence C, Pate L, Longobardi S, Wang X, James JA, Kovats S, Farris AD. Bacillus anthracis Edema Toxin Inhibits Efferocytosis in Human Macrophages and Alters Efferocytic Receptor Signaling. Int J Mol Sci. 2019 Mar 7;20(5). doi: 10.3390/ijms20051167. PubMed PMID: 30866434; PubMed Central PMCID: PMC6429438.
Yuen LH, Dana S, Liu Y, Bloom SI, Thorsell AG, Neri D, Donato AJ, Kireev D, Schüler H, Franzini RM. A Focused DNA-Encoded Chemical Library for the Discovery of Inhibitors of NAD⁺-Dependent Enzymes. J Am Chem Soc. 2019;141(13):5169–5181. doi:10.1021/jacs.8b08039
Jiang Y, Zhang Y, Leung JY, Fan C, Popov KI, Su S, Qian J, Wang X, Holtzhausen A, Ubil E, Xiang Y, Davis I, Dokholyan NV, Wu G, Perou CM, Kim WY, Earp HS, Liu P. MERTK mediated novel site Akt phosphorylation alleviates SAV1 suppression. Nat Commun. 2019;10(1):1515. Published 2019 Apr 3. doi:10.1038/s41467-019-09233-7
Blake DR, Vaseva AV, Hodge RG, Kline MP, Gilbert TSK, Tyagi V, Huang D, Whiten GC, Larson JE, Wang X, Pearce KH, Herring LE, Graves LM, Frye SV, Emanuele MJ, Cox AD, Der CJ. Application of a MYC degradation screen identifies sensitivity to CDK9 inhibitors in KRAS-mutant pancreatic cancer. Sci Signal. 2019;12(590):eaav7259. Published 2019 Jul 16. doi:10.1126/scisignal.aav7259
Ervin SM, Hanley RP, Lim L, Walton WG, Pearce KH, Bhatt AP, James LI, Redinbo MR. Targeting Regorafenib-Induced Toxicity through Inhibition of Gut Microbial β-Glucuronidases. ACS Chem Biol. 2019;14(12):2737–2744. doi:10.1021/acschembio.9b00663
Holtzhausen A, Harris W, Ubil E, Hunter DM, Zhao J, Zhang Y, Zhang D, Liu Q, Wang X, Graham DK, Frye SV, Earp HS. TAM Family Receptor Kinase Inhibition Reverses MDSC-Mediated Suppression and Augments Anti-PD-1 Therapy in Melanoma. Cancer Immunol Res. 2019;7(10):1672–1686. doi:10.1158/2326-6066.CIR-19-0008
Wong JP, Stuhlmiller TJ, Giffin LC, Lin C, Bigi R, Zhao J, Zhang W, Bravo Cruz AG, Park SI, Earp HS, Dittmer DP, Frye SV, Wang X, Johnson GL, Damania B. Kinome profiling of non-Hodgkin lymphoma identifies Tyro3 as a therapeutic target in primary effusion lymphoma. Proc Natl Acad Sci U S A. 2019;116(33):16541–16550. doi:10.1073/pnas.1903991116
Hopcraft SE, Pattenden SG, James LI, Frye S, Dittmer DP, Damania B. Chromatin remodeling controls Kaposi’s sarcoma-associated herpesvirus reactivation from latency. PLoS Pathog. 2018 Sep;14(9):e1007267. doi: 10.1371/journal.ppat.1007267. eCollection 2018 Sep. PubMed PMID: 30212584; PubMed Central PMCID: PMC6136816.