PDBsum entry 5qcm

Hydrolase/hydrolase inhibitor

PDB id: 5qcm

Contents

Protein chain

238 a.a.

Ligands

BVJ

SO4

EDO ×15

Waters ×153

PDB id:

5qcm

Name:

Hydrolase/hydrolase inhibitor

Title:

Factor xia in complex with the inhibitor methyl ~{n}-[4-[[(1~{s})-2- [(~{e})-3-[3-chloranyl-2-fluoranyl-6-(1,2,3,4-tetrazol-1-yl) phenyl]prop-2-enoyl]-3,4-dihydro-1~{h}-isoquinolin-1- yl]carbonylamino]phenyl]carbamate

Structure:

Coagulation factor xi. Chain: a. Fragment: heavy chain (unp residues 388-625). Synonym: fxi,plasma thromboplastin antecedent,pta. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: f11. Expressed in: escherichia coli. Expression_system_taxid: 469008.

Resolution:

2.20Å R-factor: 0.217 R-free: 0.244

Authors:

S.Sheriff

Key ref:

D.J.P.Pinto et al. (2017). Discovery of a Parenteral Small Molecule Coagulation Factor XIa Inhibitor Clinical Candidate (BMS-962212). J Med Chem, 60, 9703-9723. PubMed id: 29077405 DOI: 10.1021/acs.jmedchem.7b01171

Date:

10-Aug-17 Release date: 08-Nov-17

Protein chain

P03951  (FA11_HUMAN) -  Coagulation factor XI from Homo sapiens

Seq: 625 a.a.

Struc: 238 a.a.*

* PDB and UniProt seqs differ at 2 residue positions (black crosses)

Enzyme reactions

• Enzyme class: E.C.3.4.21.27 - coagulation factor XIa.
• Reaction: Selective cleavage of Arg-|-Ala and Arg-|-Val bonds in factor IX to form factor IXa.

DOI no: 10.1021/acs.jmedchem.7b01171

J Med Chem 60:9703-9723 (2017)

PubMed id: 29077405

Discovery of a Parenteral Small Molecule Coagulation Factor XIa Inhibitor Clinical Candidate (BMS-962212).

D.J.P.Pinto, M.J.Orwat, L.M.Smith, M.L.Quan, P.Y.S.Lam, K.A.Rossi, A.Apedo, J.M.Bozarth, Y.Wu, J.J.Zheng, B.Xin, N.Toussaint, P.Stetsko, O.Gudmundsson, B.Maxwell, E.J.Crain, P.C.Wong, Z.Lou, T.W.Harper, S.A.Chacko, J.E.Myers, S.Sheriff, H.Zhang, X.Hou, A.Mathur, D.A.Seiffert, R.R.Wexler, J.M.Luettgen, W.R.Ewing.

ABSTRACT

Factor XIa (FXIa) is a blood coagulation enzyme that is involved in the amplification of thrombin generation. Mounting evidence suggests that direct inhibition of FXIa can block pathologic thrombus formation while preserving normal hemostasis. Preclinical studies using a variety of approaches to reduce FXIa activity, including direct inhibitors of FXIa, have demonstrated good antithrombotic efficacy without increasing bleeding. On the basis of this potential, we targeted our efforts at identifying potent inhibitors of FXIa with a focus on discovering an acute antithrombotic agent for use in a hospital setting. Herein we describe the discovery of a potent FXIa clinical candidate, 55 (FXIa K_i= 0.7 nM), with excellent preclinical efficacy in thrombosis models and aqueous solubility suitable for intravenous administration. BMS-962212 is a reversible, direct, and highly selective small molecule inhibitor of FXIa.