6t7p
human plasmakallikrein protease domain in complex with active site directed inhibitorhuman plasmakallikrein protease domain in complex with active site directed inhibitor
Structural highlights
DiseaseKLKB1_HUMAN Defects in KLKB1 are the cause of prekallikrein deficiency (PKK deficiency) [MIM:612423; also known as Fletcher factor deficiency. This disorder is a blood coagulation defect. FunctionKLKB1_HUMAN The enzyme cleaves Lys-Arg and Arg-Ser bonds. It activates, in a reciprocal reaction, factor XII after its binding to a negatively charged surface. It also releases bradykinin from HMW kininogen and may also play a role in the renin-angiotensin system by converting prorenin into renin. Publication Abstract from PubMedThe serine protease Factor XI (FXI) is a prominent drug target as it holds promise to deliver efficacious anti-coagulation 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 1, identified from a diverse library of internal serine protease inhibitors, was originally designed as a complement Factor D inhibitor and exhibited sub-micromolar FXIa activity and an encouraging ADME profile while being devoid of peptidomimetic architecture. Optimization of interactions in the S1, S1beta, and S1` pockets of FXIa through a combination of structure-based drug design and traditional medicinal chemistry led to the discovery of compound 23 with sub-nanomolar potency on FXIa, enhanced selectivity over other coagulation proteases, and a pre-clinical PK profile consistent with bid dosing in patients. Structure-based design and pre-clinical characterization of selective and orally bioavailable Factor XIa inhibitors: Demonstrating the power of an integrated S1 protease family approach.,Lorthiois E, Roache J, Barnes-Seeman D, Altmann E, Hassiepen U, Turner G, Duvadie R, Hornak V, Karki RG, Schiering N, Weihofen WA, 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 YH, 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 RC, Maibaum J, Adams CM J Med Chem. 2020 Jun 17. doi: 10.1021/acs.jmedchem.0c00279. PMID:32551603[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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