Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTMF8H9)

• DTT Name: Plasma kallikrein (KLKB1)
• Synonyms: Plasma prekallikrein; Plasma kallikrein light chain; Plasma kallikrein heavy chain; PKK; Kininogenin; KLK3; Fletcher factor
• Gene Name: KLKB1
• DTT Type: Successful target; [1]
• BioChemical Class: Peptidase
• UniProt ID: KLKB1_HUMAN
• TTD ID: T82739
• EC Number: EC 3.4.21.34
• Sequence:
  MILFKQATYFISLFATVSCGCLTQLYENAFFRGGDVASMYTPNAQYCQMRCTFHPRCLLF
  SFLPASSINDMEKRFGCFLKDSVTGTLPKVHRTGAVSGHSLKQCGHQISACHRDIYKGVD
  MRGVNFNVSKVSSVEECQKRCTNNIRCQFFSYATQTFHKAEYRNNCLLKYSPGGTPTAIK
  VLSNVESGFSLKPCALSEIGCHMNIFQHLAFSDVDVARVLTPDAFVCRTICTYHPNCLFF
  TFYTNVWKIESQRNVCLLKTSESGTPSSSTPQENTISGYSLLTCKRTLPEPCHSKIYPGV
  DFGGEELNVTFVKGVNVCQETCTKMIRCQFFTYSLLPEDCKEEKCKCFLRLSMDGSPTRI
  AYGTQGSSGYSLRLCNTGDNSVCTTKTSTRIVGGTNSSWGEWPWQVSLQVKLTAQRHLCG
  GSLIGHQWVLTAAHCFDGLPLQDVWRIYSGILNLSDITKDTPFSQIKEIIIHQNYKVSEG
  NHDIALIKLQAPLNYTEFQKPICLPSKGDTSTIYTNCWVTGWGFSKEKGEIQNILQKVNI
  PLVTNEECQKRYQDYKITQRMVCAGYKEGGKDACKGDSGGPLVCKHNGMWRLVGITSWGE
  GCARREQPGVYTKVAEYMDWILEKTQSSDGKAQMQSPA
• Function: 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. The enzyme cleaves Lys-Arg and Arg-Ser bonds.
• KEGG Pathway: Complement and coagulation cascades (hsa04610)
• Reactome Pathway:
  Activation of Matrix Metalloproteinases (R-HSA-1592389)
  Intrinsic Pathway of Fibrin Clot Formation (R-HSA-140837)

Molecular Interaction Atlas (MIA) of This DTT

3 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Berotralstat	DMWA2DZ	Hereditary angioedema	4A00.14	Approved	[2]
Ecallantide	DMOF2C6	Retina venous occlusion	9B74.1	Approved	[1]
Lanadelumab	DMEH7YU	Hereditary angioedema	4A00.14	Approved	[3]

3 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
KVD001	DMK4VOU	Diabetic macular edema	9B71.02	Phase 2	[4]
KVD824	DM5N4OA	Diabetic macular edema	9B71.02	Phase 2	[5]
THR-149	DMW8X05	Diabetic macular edema	9B71.02	Phase 2	[6]

8 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
(3,4-dichlorophenyl)(1H-pyrazol-1-yl)methanone	DMNVDLI	Discovery agent	N.A.	Investigative	[7]
(3-nitro-1H-pyrazol-1-yl)(p-tolyl)methanone	DMT9FZD	Discovery agent	N.A.	Investigative	[7]
(3-nitro-1H-pyrazol-1-yl)(phenyl)methanone	DMD4Z6H	Discovery agent	N.A.	Investigative	[7]
(4-bromo-1H-pyrazol-1-yl)(p-tolyl)methanone	DM31OSD	Discovery agent	N.A.	Investigative	[7]
1-benzoyl-N-phenyl-1H-pyrazole-3-carboxamide	DMG5MNZ	Discovery agent	N.A.	Investigative	[7]
D-Pro-Phe-Arg chloromethyl ketone	DMRJQ8X	Discovery agent	N.A.	Investigative	[8]
ZK-810388	DMNOWAQ	Discovery agent	N.A.	Investigative	[9]
ZK-814048	DMCBV5F	Discovery agent	N.A.	Investigative	[9]

References

• [1] Ecallantide (DX-88), a plasma kallikrein inhibitor for the treatment of hereditary angioedema and the prevention of blood loss in on-pump cardiothoracic surgery. Expert Opin Biol Ther. 2008 Aug;8(8):1187-99.
• [2] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services. 2020
• [3] 2018 FDA drug approvals.Nat Rev Drug Discov. 2019 Feb;18(2):85-89.
• [4] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [5] Clinical pipeline report, company report or official report of KalVista Pharmaceuticals.
• [6] Clinical pipeline report, company report or official report of Oxurion.
• [7] N-benzoylpyrazoles are novel small-molecule inhibitors of human neutrophil elastase. J Med Chem. 2007 Oct 4;50(20):4928-38.
• [8] Novel 3-carboxamide-coumarins as potent and selective FXIIa inhibitors. J Med Chem. 2008 Jun 12;51(11):3077-80.
• [9] Thiophene-anthranilamides as highly potent and orally available factor Xa inhibitors. J Med Chem. 2007 Jun 28;50(13):2967-80.