Discovery of a Potent and Selective in Vivo Probe (GNE-272) for the Bromodomains of CBP/EP300

Journal of Medicinal Chemistry

Volumn 59, Issue 23, 2016, Pages 10549-10563

  Crawford, Terry D ^a   Romero, F Anthony ^a   Lai, Kwong Wah ^b   Tsui, Vickie ^a   Taylor, Alexander M ^c   De Leon Boenig, Gladys ^a   Noland, Cameron L ^a   Murray, Jeremy ^a   Ly, Justin ^a   Choo, Edna F ^a   Hunsaker, Thomas L ^a   Chan, Emily W ^a   Merchant, Mark ^a   Kharbanda, Samir ^a   Gascoigne, Karen E ^a   Kaufman, Susan ^a   Beresini, Maureen H ^a   Liao, Jiangpeng ^b   Liu, Wenfeng ^b   Chen, Kevin X ^b   Chen, Zhongguo ^b   Conery, Andrew R ^c   Côté, Alexandre ^c   Jayaram, Hariharan ^c   Jiang, Ying ^b   Kiefer, James R ^a   Kleinheinz, Tracy ^a   Li, Yingjie ^b   Maher, Jonathan ^a   Pardo, Eneida ^c   Poy, Florence ^c   Spillane, Kerry L ^c   Wang, Fei ^b   Wang, Jian ^b   Wei, Xiaocang ^b   Xu, Zhaowu ^b   Xu, Zhongya ^b   Yen, Ivana ^a   Zawadzke, Laura ^c   Zhu, Xiaoyu ^b   Bellon, Steven ^c   Cummings, Richard ^c   Cochran, Andrea G ^a   Albrecht, Brian K ^c   Magnuson, Steven ^a   more..

^a GENENTECH INC   (United States)

^b WUXI APPTEC   (China)

^c Department of Structural Biology   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

1 [3 [[2 FLUORO 4 (1 METHYL 1 H PYRAZOL 4 YL)PHENYL]AMINO] 1 (TETRAHYDROFURAN 3 YL) 6,7 DIHYDRO 1 H PYRAZOLO[4,3 C]PYRIDIN 5(4H) YL]ETHANONE; ANTINEOPLASTIC AGENT; BROMODOMAIN INHIBITOR; CYCLIC AMP RESPONSIVE ELEMENT BINDING PROTEIN BINDING PROTEIN; E1A ASSOCIATED P300 PROTEIN; LYSINE; MYC PROTEIN; UNCLASSIFIED DRUG; GEN-272; HISTONE ACETYLTRANSFERASE PCAF; PYRAZOLE DERIVATIVE; PYRIDONE DERIVATIVE;

ACUTE MYELOID LEUKEMIA; ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ANTINEOPLASTIC ACTIVITY; ANTIPROLIFERATIVE ACTIVITY; AREA UNDER THE CURVE; ARTICLE; CANCER CELL LINE; CONTROLLED STUDY; CRYSTAL STRUCTURE; DOSE RESPONSE; DRUG BINDING SITE; DRUG BLOOD LEVEL; DRUG DESIGN; DRUG DOSE COMPARISON; DRUG EFFICACY; DRUG HALF LIFE; DRUG MECHANISM; DRUG PENETRATION; DRUG POTENCY; DRUG SCREENING; DRUG SELECTIVITY; DRUG STRUCTURE; DRUG SYNTHESIS; DRUG TARGETING; EC50; GENE EXPRESSION REGULATION; HEPATIC CLEARANCE; IC50; IN VITRO STUDY; IN VIVO STUDY; LIVER CELL; MAXIMUM PLASMA CONCENTRATION; METABOLIC STABILITY; MOUSE; NONHUMAN; STRUCTURE ACTIVITY RELATION; VOLUME OF DISTRIBUTION; ANIMAL; ANTAGONISTS AND INHIBITORS; CELL PROLIFERATION; CHEMICAL STRUCTURE; CHEMISTRY; DOG; DRUG DEVELOPMENT; DRUG EFFECTS; FEMALE; HUMAN; MDCK CELL LINE; MOLECULAR MODEL; NUDE MOUSE; SYNTHESIS; TUMOR CELL LINE;

ANIMALS; ANTINEOPLASTIC AGENTS; CELL LINE, TUMOR; CELL PROLIFERATION; DOGS; DOSE-RESPONSE RELATIONSHIP, DRUG; DRUG DISCOVERY; DRUG SCREENING ASSAYS, ANTITUMOR; FEMALE; HUMANS; MADIN DARBY CANINE KIDNEY CELLS; MICE; MICE, NUDE; MODELS, MOLECULAR; MOLECULAR STRUCTURE; P300-CBP TRANSCRIPTION FACTORS; PYRAZOLES; PYRIDONES; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 85003706736     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/acs.jmedchem.6b01022     Document Type: Article

References (27)

1. Romero, F. A.; Taylor, A. M.; Crawford, T. D.; Tsui, V.; Côté, A.; Magnuson, S. Disrupting Acetyl-Lysine Recognition: Progress in the Development of Bromodomain Inhibitors J. Med. Chem. 2016, 59, 1271-1298 10.1021/acs.jmedchem.5b01514
2. Theodoulou, N. H.; Tomkinson, N. C. O.; Prinjha, R. K.; Humphreys, P. G. Progress in the Development of Non-BET Bromodomain Chemical Probes ChemMedChem 2016, 11, 477-487 10.1002/cmdc.201500540
3. Taylor, A. M.; Côté, A.; Hewitt, M. C.; Pastor, R.; Leblanc, Y.; Nasveschuk, C. G.; Romero, F. A.; Crawford, T. D.; Cantone, N.; Jayaram, H.; Setser, J.; Murray, J.; Beresini, M. H.; de Leon Boenig, G.; Chen, Z.; Conery, A. R.; Cummings, R. T.; Dakin, L. A.; Flynn, E. M.; Huang, O. W.; Kaufman, S.; Keller, P. J.; Kiefer, J. R.; Lai, T.; Li, Y.; Liao, J.; Liu, W.; Lu, H.; Pardo, E.; Tsui, V.; Wang, J.; Wang, Y.; Xu, Z.; Yan, F.; Yu, D.; Zawadzke, L.; Zhu, X.; Zhu, X.; Sims, R. J., III; Cochran, A. G.; Bellon, S.; Audia, J. E.; Magnuson, S.; Albrecht, B. K. Fragment-Based Discovery of a Selective and Cell-Active Benzodiazepinone CBP/EP300 Bromodomain Inhibitor (CPI-637) ACS Med. Chem. Lett. 2016, 7, 531-536 10.1021/acsmedchemlett.6b00075
4. Crawford, T. D.; Tsui, V.; Flynn, E. M.; Wang, S.; Taylor, A. M.; Côté, A.; Audia, J. E.; Beresini, M. H.; Burdick, D. J.; Cummings, R. T.; Dakin, L. A.; Duplessis, M.; Good, A. C.; Hewitt, M. C.; Huang, H.-R.; Jayaram, H.; Kiefer, J. R.; Jiang, Y.; Murray, J. M.; Nasveschuk, C. G.; Pardo, E.; Poy, F.; Romero, F. A.; Tang, Y.; Wang, J.; Xu, Z.; Zawadzke, L. E.; Zhu, X.; Albrecht, B. K.; Magnuson, S. R.; Bellon, S. F.; Cochran, A. G. Diving Into the Water: Inducible Binding Conformations for BRD4, TAF1(2), BRD9, and CECR2 Bromodomains J. Med. Chem. 2016, 59, 5391-5402 10.1021/acs.jmedchem.6b00264
5. Delvecchio, M.; Gaucher, J.; Aguilar-Gurrieri, C.; Ortega, E.; Panne, D. Structure of the P300 Catalytic Core and Implications for Chromatin Targeting and HAT Regulation Nat. Struct. Mol. Biol. 2013, 20, 1040-1046 10.1038/nsmb.2642
6. Mujtaba, S.; He, Y.; Zeng, L.; Yan, S.; Plotnikova, O.; Sachchidanand; Sanchez, R.; Zeleznik-Le, N. J.; Ronai, Z.; Zhou, M. M. Structural Mechanism of the Bromodomain of the Coactivator CBP in P53 Transcriptional Activation Mol. Cell 2004, 13, 251-263 10.1016/S1097-2765(03)00528-8
7. Ianculescu, I.; Wu, D. Y.; Siegmund, K. D.; Stallcup, M. R. Selective Roles for cAMP Response Element-Binding Protein Binding Protein and P300 Protein as Coregulators for Androgen-Regulated Gene Expression in Advanced Prostate Cancer Cells J. Biol. Chem. 2012, 287, 4000-4013 10.1074/jbc.M111.300194
8. Iyer, N. G.; Ozdag, H.; Caldas, C. P300/CBP and Cancer Oncogene 2004, 23, 4225-4231 10.1038/sj.onc.1207118
9. Faiola, F.; Liu, X.; Lo, S.; Pan, S.; Zhang, K.; Lymar, E.; Farina, A.; Martinez, E. Dual Regulation of C-Myc by P300 via Acetylation-Dependent Control of Myc Protein Turnover and Coactivation of Myc-Induced Transcription Mol. Cell. Biol. 2005, 25, 10220-10234 10.1128/MCB.25.23.10220-10234.2005
10. Conery, A. R.; Centore, R. C.; Neiss, A.; Keller, P. J.; Joshi, S.; Spillane, K. L.; Sandy, P.; Hatton, C.; Pardo, E.; Zawadzke, L.; Bommi-Reddy, A.; Gascoigne, K. E.; Bryant, B. M.; Mertz, J. A.; Sims, R. J. Bromodomain Inhibition of the Transcriptional Coactivators CBP/EP300 as a Therapeutic Strategy to Target the IRF4 Network in Multiple Myeloma eLife 2016, 5, e10483 10.7554/eLife.10483
11. Ghosh, S.; Taylor, A.; Chin, M.; Huang, H.-R.; Conery, A. R.; Mertz, J. A.; Salmeron, A.; Dakle, P. J.; Mele, D.; Côté, A.; Jayaram, H.; Setser, J. W.; Poy, F.; Hatzivassiliou, G.; DeAlmeida-Nagata, D.; Sandy, P.; Hatton, C.; Romero, F. A.; Chiang, E.; Reimer, T.; Crawford, T.; Pardo, E.; Watson, V. G.; Tsui, V.; Cochran, A. G.; Zawadzke, L.; Harmange, J.-C.; Audia, J. E.; Bryant, B. M.; Cummings, R. T.; Magnuson, S. R.; Grogan, J. L.; Bellon, S. F.; Albrecht, B. K.; Sims, R. J., III; Lora, J. M. Regulatory T Cell Modulation by CBP/EP300 Bromodomain Inhibition J. Biol. Chem. 2016, 291, 13014-13027 10.1074/jbc.M115.708560
12. Chekler, E. L. P.; Pellegrino, J. A.; Lanz, T. A.; Denny, R. A.; Flick, A. C.; Coe, J.; Langille, J.; Basak, A.; Liu, S.; Stock, I. A.; Sahasrabudhe, P.; Bonin, P. D.; Lee, K.; Pletcher, M. T.; Jones, L. H. Transcriptional Profiling of a Selective CREB Binding Protein Bromodomain Inhibitor Highlights Therapeutic Opportunities Chem. Biol. 2015, 22, 1588-1596 10.1016/j.chembiol.2015.10.013
13. Rooney, T. P. C.; Filippakopoulos, P.; Fedorov, O.; Picaud, S.; Cortopassi, W. A.; Hay, D. A.; Martin, S.; Tumber, A.; Rogers, C. M.; Philpott, M.; Wang, M.; Thompson, A. L.; Heightman, T. D.; Pryde, D. C.; Cook, A.; Paton, R. S.; Müller, S.; Knapp, S.; Brennan, P. E.; Conway, S. J. A Series of Potent CREBBP Bromodomain Ligands Reveals an Induced-Fit Pocket Stabilized by a Cation-Π Interaction Angew. Chem., Int. Ed. 2014, 53, 6126-6130 10.1002/anie.201402750
14. Hay, D. A.; Fedorov, O.; Martin, S.; Singleton, D. C.; Tallant, C.; Wells, C.; Picaud, S.; Philpott, M.; Monteiro, O. P.; Rogers, C. M.; Conway, S. J.; Rooney, T. P. C.; Tumber, A.; Yapp, C.; Filippakopoulos, P.; Bunnage, M. E.; Müller, S.; Knapp, S.; Schofield, C. J.; Brennan, P. E. Discovery and Optimization of Small-Molecule Ligands for the CBP/P300 Bromodomains J. Am. Chem. Soc. 2014, 136, 9308-9319 10.1021/ja412434f
15. I-CBP112: A CREBBP/EP300-Selective Chemical Probe; SGC: Oxford, UK, 2015; http://www.thesgc.org/chemical-probes/I-CBP112 (accessed June 16, 2016).
16. Unzue, A.; Xu, M.; Dong, J.; Wiedmer, L.; Spiliotopoulos, D.; Caflisch, A.; Nevado, C. Fragment-Based Design of Selective Nanomolar Ligands of the CREBBP Bromodomain J. Med. Chem. 2016, 59, 1350-1356 10.1021/acs.jmedchem.5b00172
17. Picaud, S.; Fedorov, O.; Thanasopoulou, A.; Leonards, K.; Jones, K.; Meier, J.; Olzscha, H.; Monteiro, O.; Martin, S.; Philpott, M.; Tumber, A.; Filippakopoulos, P.; Yapp, C.; Wells, C.; Che, K. H.; Bannister, A.; Robson, S.; Kumar, U.; Parr, N.; Lee, K.; Lugo, D.; Jeffrey, P.; Taylor, S.; Vecellio, M. L.; Bountra, C.; Brennan, P. E.; O’Mahony, A.; Velichko, S.; Müller, S.; Hay, D.; Daniels, D. L.; Urh, M.; La Thangue, N. B.; Kouzarides, T.; Prinjha, R.; Schwaller, J.; Knapp, S. Generation of a Selective Small Molecule Inhibitor of the CBP/P300 Bromodomain for Leukemia Therapy Cancer Res. 2015, 75, 5106-5119 10.1158/0008-5472.CAN-15-0236
18. Hammitzsch, A.; Tallant, C.; Fedorov, O.; O’Mahony, A.; Brennan, P. E.; Hay, D. A.; Martinez, F. O.; Al-Mossawi, M. H.; de Wit, J.; Vecellio, M.; Wells, C.; Wordsworth, P.; Müller, S.; Knapp, S.; Bowness, P. CBP30, a Selective CBP/P300 Bromodomain Inhibitor, Suppresses Human Th17 Responses Proc. Natl. Acad. Sci. U. S. A. 2015, 112, 10768-10773 10.1073/pnas.1501956112
19. Hewitt, M. C.; Leblanc, Y.; Gehling, V. S.; Vaswani, R. G.; Côté, A.; Nasveschuk, C. G.; Taylor, A. M.; Harmange, J.-C.; Audia, J. E.; Pardo, E.; Cummings, R.; Joshi, S.; Sandy, P.; Mertz, J. A.; Sims, R. J., III; Bergeron, L.; Bryant, B. M.; Bellon, S.; Poy, F.; Jayaram, H.; Tang, Y.; Albrecht, B. K. Development of Methyl Isoxazoleazepines as Inhibitors of BET Bioorg. Med. Chem. Lett. 2015, 25, 1842-1848 10.1016/j.bmcl.2015.03.045
20. Taylor, A. M.; Vaswani, R. G.; Gehling, V. S.; Hewitt, M. C.; Leblanc, Y.; Audia, J. E.; Bellon, S.; Cummings, R. T.; Côté, A.; Harmange, J.-C.; Jayaram, H.; Joshi, S.; Lora, J. M.; Mertz, J. A.; Neiss, A.; Pardo, E.; Nasveschuk, C. G.; Poy, F.; Sandy, P.; Setser, J. W.; Sims, R. J., III; Tang, Y.; Albrecht, B. K. Discovery of Benzotriazolo[4,3-D][1,4]Diazepines as Orally Active Inhibitors of BET Bromodomains ACS Med. Chem. Lett. 2016, 7, 145-150 10.1021/ml500411h
21. Beresini, M. H.; Liu, Y.; Dawes, T. D.; Clark, K. R.; Orren, L.; Schmidt, S.; Turincio, R.; Jones, S. W.; Rodriguez, R. A.; Thana, P.; Hascall, D.; Gross, D. P.; Skelton, N. J. Small-Molecule Library Subset Screening as an Aid for Accelerating Lead Identification J. Biomol. Screening 2014, 19, 758-770 10.1177/1087057114522515
22. MoKa; Molecular Discovery: Perugia, Italy; www.moldiscovery.com/software/moka/ (accessed June 16, 2016).
23. Hagemans, D.; van Belzen, I. A. E. M.; Morán Luengo, T.; Rüdiger, S. G. D. A Script to Highlight Hydrophobicity and Charge on Protein Surfaces Front. Mol. Biosci. 2015, 2, 1-11 10.3389/fmolb.2015.00056
24. Albrecht, B. K.; Gehling, V. S.; Hewitt, M. C.; Vaswani, R. G.; Côté, A.; Leblanc, Y.; Nasveschuk, C. G.; Bellon, S.; Bergeron, L.; Campbell, R.; Cantone, N.; Cooper, M. R.; Cummings, R. T.; Jayaram, H.; Joshi, S.; Mertz, J. A.; Neiss, A.; Normant, E.; O’Meara, M.; Pardo, E.; Poy, F.; Sandy, P.; Supko, J.; Sims, R. J., III; Harmange, J.-C.; Taylor, A. M.; Audia, J. E. Identification of a Benzoisoxazoloazepine Inhibitor (CPI-0610) of the Bromodomain and Extra-Terminal (BET) Family as a Candidate for Human Clinical Trials J. Med. Chem. 2016, 59, 1330-1339 10.1021/acs.jmedchem.5b01882
25. Halladay, J. S.; Wong, S.; Jaffer, S. M.; Sinhababu, A. K.; Khojasteh-Bakht, S. C. Metabolic Stability Screen for Drug Discovery Using Cassette Analysis and Column Switching Drug Metab. Lett. 2007, 1, 67-72 10.2174/187231207779814364
26. Obach, R. S.; Baxter, J. G.; Liston, T. E.; Silber, B. M.; Jones, B. C.; Macintyre, F.; Rance, D. J.; Wastall, P. The Prediction of Human Pharmacokinetic Parameters From Preclinical and in Vitro Metabolism Data J. Pharmacol. Exp. Ther. 1997, 283, 46-58
27. Halladay, J. S.; Delarosa, E. M.; Tran, D.; Wang, L.; Wong, S.; Khojasteh, S. C. High-Throughput, 384-Well, LC-MS/MS CYP Inhibition Assay Using Automation, Cassette-Analysis Technique and Streamlined Data Analysis Drug Metab. Lett. 2011, 5, 220-230 10.2174/187231211796905017