6TS4

Coagulation factor XI protease domain in complex with active site inhibitor

Summary for 6TS4

• Entry DOI: 10.2210/pdb6ts4/pdb
• Related: 6T7P
• Descriptor: Coagulation factor XI, SULFATE ION, DIMETHYL SULFOXIDE, ... (6 entities in total)
• Functional Keywords: s1 protease, serine protease, structure-based drug design, active site directed inhibitor, hydrolase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 27902.75

Authors

Renatus, M.,Schiering, N. (deposition date: 2019-12-19, release date: 2020-07-08, Last modification date: 2020-08-26)

Primary citation

Lorthiois, E.,Roache, J.,Barnes-Seeman, D.,Altmann, E.,Hassiepen, U.,Turner, G.,Duvadie, R.,Hornak, V.,Karki, R.G.,Schiering, N.,Weihofen, W.A.,Perruccio, F.,Calhoun, A.,Fazal, T.,Dedic, D.,Durand, C.,Dussauge, S.,Fettis, K.,Tritsch, F.,Dentel, C.,Druet, A.,Liu, D.,Kirman, L.,Lachal, J.,Namoto, K.,Bevan, D.,Mo, R.,Monnet, G.,Muller, L.,Zessis, R.,Huang, X.,Lindsley, L.,Currie, T.,Chiu, Y.H.,Fridrich, C.,Delgado, P.,Wang, S.,Hollis-Symynkywicz, M.,Berghausen, J.,Williams, E.,Liu, H.,Liang, G.,Kim, H.,Hoffmann, P.,Hein, A.,Ramage, P.,D'Arcy, A.,Harlfinger, S.,Renatus, M.,Ruedisser, S.,Feldman, D.,Elliott, J.,Sedrani, R.,Maibaum, J.,Adams, C.M.
Structure-Based Design and Preclinical Characterization of Selective and Orally Bioavailable Factor XIa Inhibitors: Demonstrating the Power of an Integrated S1 Protease Family Approach.
J.Med.Chem., 63:8088-8113, 2020

PubMed Abstract: The serine protease factor XI (FXI) is a prominent drug target as it holds promise to deliver efficacious anticoagulation without an enhanced risk of major bleeds. Several efforts have been described targeting the active form of the enzyme, FXIa. Herein, we disclose our efforts to identify potent, selective, and orally bioavailable inhibitors of FXIa. Compound , identified from a diverse library of internal serine protease inhibitors, was originally designed as a complement factor D inhibitor and exhibited submicromolar FXIa activity and an encouraging absorption, distribution, metabolism, and excretion (ADME) profile while being devoid of a peptidomimetic architecture. Optimization of interactions in the S1, S1β, and S1' pockets of FXIa through a combination of structure-based drug design and traditional medicinal chemistry led to the discovery of compound with subnanomolar potency on FXIa, enhanced selectivity over other coagulation proteases, and a preclinical pharmacokinetics (PK) profile consistent with bid dosing in patients.

PubMed: 32551603
DOI: 10.1021/acs.jmedchem.0c00279

Experimental method

X-RAY DIFFRACTION (1.17 Å)