Novel Autotaxin Inhibitor for the Treatment of Idiopathic Pulmonary Fibrosis: A Clinical Candidate Discovered Using DNA-Encoded Chemistry

被引：87

作者：

Cuozzo, John W. ^{[1
]}

Clark, Matthew A. ^{[1
]}

Keefe, Anthony D. ^{[1
]}

Kohlmann, Anna ^{[1
]}

Mulvihill, Mark ^{[2
]}

Ni, Haihong ^{[3
]}

Renzetti, Louis M. ^{[2
]}

Resnicow, Daniel, I ^{[1
]}

Ruebsam, Frank ^{[3
]}

Sigel, Eric A. ^{[1
]}

Thomson, Heather A. ^{[1
]}

Wang, Ce ^{[3
]}

Xie, Zhifeng ^{[3
]}

Zhang, Ying ^{[1
]}

机构：

[1] XChem Inc, Waltham, MA 02543 USA

[2] XRx Inc, New York, NY 10016 USA

[3] BioDuro LLC, Beijing 102206, Peoples R China

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2020年 / 63卷 / 14期

关键词：

ENZYME;

D O I：

10.1021/acs.jmedchem.0c00688

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The activity of the secreted phosphodiesterase autotaxin produces the inflammatory signaling molecule LPA and has been associated with a number of human diseases including idiopathic pulmonary fibrosis (IPF). We screened a single DNA-encoded chemical library (DECL) of 225 million compounds and identified a series of potent inhibitors. Optimization of this series led to the discovery of compound 1 (X-165), a highly potent, selective, and bioavailable small molecule. Cocrystallization of compound 1 with human autotaxin demonstrated that it has a novel binding mode occupying both the hydrophobic pocket and a channel near the autotaxin active site. Compound 1 inhibited the production of LPA in human and mouse plasma at nanomolar levels and showed efficacy in a mouse model of human lung fibrosis. After successfully completing IND-enabling studies, compound 1 was approved by the FDA for a Phase I clinical trial. These results demonstrate that DECL hits can be readily optimized into clinical candidates.

引用

页码：7840 / 7856

页数：17

共 23 条

[1] Discovering Drugs with DNA-Encoded Library Technology: From Concept to Clinic with an Inhibitor of Soluble Epoxide Hydrolase [J].

Belyanskaya, Svetlana L. ;

Ding, Yun ;

Callahan, James F. ;

Lazaar, Aili L. ;

Israel, David I. .

CHEMBIOCHEM, 2017, 18 (09) :837-842

[2] Coming of Age for Autotaxin and Lysophosphatidate Signaling: Clinical Applications for Preventing, Detecting and Targeting Tumor-Promoting Inflammation [J].

Benesch, Matthew G. K. ;

MacIntyre, Iain T. K. ;

McMullen, Todd P. W. ;

Brindley, David N. .

CANCERS, 2018, 10 (03)

[3]

Daccord C., 2016, F1000RES

[4] Discovery of 2-[[2-Ethyl-6-[4-[2-(3-hydroxyazetidin-1-yl)-2-oxoethyl]piperazin-1-yl]-8-methylimidazo[1,2-a]pyridin-3-yl]methylamino]-4-(4-fluorophenyl)thiazole-5-carbonitrile (GLPG1690), a First-in-Class Autotaxin Inhibitor Undergoing Clinical Evaluation for the Treatment of Idiopathic Pulmonary Fibrosis [J].

Desroy, Nicolas ;

Housseman, Christopher ;

Bock, Xavier ;

Joncour, Agnes ;

Bienvenu, Natacha ;

Cherel, Laetitia ;

Labeguere, Virginie ;

Rondet, Emilie ;

Peixoto, Christophe ;

Grassot, Jean-Marie ;

Picolet, Olivier ;

Annoott, Denis ;

Triballeau, Nicolas ;

Monjardet, Alain ;

Wakselman, Emanuelle ;

Roncoroni, Veronique ;

Le Tallec, Sandrine ;

Blanque, Roland ;

Cottereaux, Celine ;

Vandervoort, Nele ;

Christophe, Thierry ;

Mollat, Patrick ;

Lamers, Marieke ;

Auberval, Marielle ;

Hrvacic, Boska ;

Ralic, Jovica ;

Oste, Line ;

van der Aar, Ellen ;

Brys, Reginald ;

Heckmann, Bertrand .

JOURNAL OF MEDICINAL CHEMISTRY, 2017, 60 (09) :3580-3590

[5] DNA-encoded chemistry: enabling the deeper sampling of chemical space [J].

Goodnow, Robert A., Jr. ;

Dumelin, Christoph E. ;

Keefe, Anthony D. .

NATURE REVIEWS DRUG DISCOVERY, 2017, 16 (02) :131-147

[6] Lysophosphatidic acid and autotaxin stimulate cell motility of neoplastic and non-neoplastic cells through LPA1 [J].

Hama, K ;

Aoki, J ;

Fukaya, M ;

Kishi, Y ;

Sakai, T ;

Suzuki, R .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2004, 279 (17) :17634-17639

[7] Discovery of a First-in-Class Receptor Interacting Protein 1 (RIP1) Kinase Specific Clinical Candidate (GSK2982772) for the Treatment of Inflammatory Diseases [J].

Harris, Philip A. ;

Berger, Scott B. ;

Jeong, Jae U. ;

Nagilla, Rakesh ;

Bandyopadhyay, Deepak ;

Campobasso, Nino ;

Capriotti, Carol A. ;

Cox, Julie A. ;

Dare, Lauren ;

Dong, Xiaoyang ;

Eidam, Patrick M. ;

Finger, Joshua N. ;

Hoffman, Sandra J. ;

Kang, James ;

Kasparcova, Viera ;

King, Bryan W. ;

Lehr, Ruth ;

Lan, Yunfeng ;

Leister, Lara K. ;

Lich, John D. ;

MacDonald, Thomas T. ;

Miller, Nathan A. ;

Ouellette, Michael T. ;

Pao, Christina S. ;

Rahman, Attiq ;

Reilly, Michael A. ;

Rendina, Alan R. ;

Rivera, Elizabeth J. ;

Schaeffer, Michelle C. ;

Sehon, Clark A. ;

Singhaus, Robert R. ;

Sun, Helen H. ;

Swift, Barbara A. ;

Totoritis, Rachel D. ;

Vossenkaemper, Anna ;

Ward, Paris ;

Wisnoski, David D. ;

Zhang, Daohua ;

Marquis, Robert W. ;

Gough, Peter J. ;

Bertin, John .

JOURNAL OF MEDICINAL CHEMISTRY, 2017, 60 (04) :1247-1261

[8] DNA-Encoded Library Screening Identifies Benzo[b][1,4]oxazepin-4-ones as Highly Potent and Monoselective Receptor Interacting Protein 1 Kinase Inhibitors [J].

Harris, Philip A. ;

King, Bryan W. ;

Bandyopadhyay, Deepak ;

Berger, Scott B. ;

Campobasso, Nino ;

Capriotti, Carol A. ;

Cox, Julie A. ;

Dare, Lauren ;

Dong, Xiaoyang ;

Finger, Joshua N. ;

Grady, LaShadric C. ;

Hoffmann, Sandra J. ;

Jeong, Jae U. ;

Kang, James ;

Kasparcova, Viera ;

Lakdawala, Ami S. ;

Lehr, Ruth ;

McNulty, Dean E. ;

Nagilla, Rakesh ;

Ouellette, Michael T. ;

Pao, Christina S. ;

Rendina, Alan R. ;

Schaeffer, Michelle C. ;

Summerfield, Jennifer D. ;

Swift, Barbara A. ;

Totoritis, Rachel D. ;

Ward, Paris ;

Zhang, Aming ;

Zhang, Daohua ;

Marquis, Robert W. ;

Bertin, John ;

Gough, Peter J. .

JOURNAL OF MEDICINAL CHEMISTRY, 2016, 59 (05) :2163-2178

[9] Autotaxin in liver fibrosis [J].

Ikeda, Hitoshi ;

Yatomi, Yutaka .

CLINICA CHIMICA ACTA, 2012, 413 (23-24) :1817-1821

[10] Novel Autotaxin Inhibitors for the Treatment of Osteoarthritis Pain: Lead Optimization via Structure-Based Drug Design [J].

Jones, Spencer B. ;

Pfeifer, Lance A. ;

Bleisch, Thomas J. ;

Beauchamp, Thomas J. ;

Durbin, Jim D. ;

Klimkowski, V. Joseph ;

Hughes, Norman E. ;

Rito, Christopher J. ;

Dao, Yen ;

Gruber, Joseph M. ;

Bui, Hai ;

Chambers, Mark G. ;

Chandrasekhar, Srinivasan ;

Lin, Chaohua ;

McCann, Denis J. ;

Mudra, Daniel R. ;

Oskins, Jennifer L. ;

Swearingen, Craig A. ;

Thirunavukkarasu, Kannan ;

Norman, Bryan H. .

ACS MEDICINAL CHEMISTRY LETTERS, 2016, 7 (09) :857-861

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