Details of the Drug Therapeutic Target (DTT)

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

• DTT Name: Caspase-1 (CASP1)
• Synonyms: P45; Interleukin-1 beta-converting enzyme; Interleukin-1 beta converting enzyme; Interleukin-1 beta convertase; IL1BCE; IL1BC; IL-1BC; IL-1 beta-converting enzyme; IL-1 beta converting enzyme; ICE; CASP-1
• Gene Name: CASP1
• DTT Type: Clinical trial target; [1]
• BioChemical Class: Peptidase
• UniProt ID: CASP1_HUMAN
• TTD ID: T98269
• EC Number: EC 3.4.22.36
• Sequence:
  MADKVLKEKRKLFIRSMGEGTINGLLDELLQTRVLNKEEMEKVKRENATVMDKTRALIDS
  VIPKGAQACQICITYICEEDSYLAGTLGLSADQTSGNYLNMQDSQGVLSSFPAPQAVQDN
  PAMPTSSGSEGNVKLCSLEEAQRIWKQKSAEIYPIMDKSSRTRLALIICNEEFDSIPRRT
  GAEVDITGMTMLLQNLGYSVDVKKNLTASDMTTELEAFAHRPEHKTSDSTFLVFMSHGIR
  EGICGKKHSEQVPDILQLNAIFNMLNTKNCPSLKDKPKVIIIQACRGDSPGVVWFKDSVG
  VSGNLSLPTTEEFEDDAIKKAHIEKDFIAFCSSTPDNVSWRHPTMGSVFIGRLIEHMQEY
  ACSCDVEEIFRKVRFSFEQPDGRAQMPTTERVTLTRCFYLFPGH
• Function: Important for defense against pathogens. Cleaves and activates sterol regulatory element binding proteins (SREBPs). Can also promote apoptosis. Upon inflammasome activation, during DNA virus infection but not RNA virus challenge, controls antiviral immunity through the cleavage of CGAS, rendering it inactive. Thiol protease that cleaves IL-1 beta between an Asp and an Ala, releasing the mature cytokine which is involved in a variety of inflammatory processes.
• KEGG Pathway:
  NOD-like receptor signaling pathway (hsa04621)
  Cytosolic DNA-sensing pathway (hsa04623)
  Amyotrophic lateral sclerosis (ALS) (hsa05014)
  Salmonella infection (hsa05132)
  Pertussis (hsa05133)
  Legionellosis (hsa05134)
  Influenza A (hsa05164)
• Reactome Pathway:
  Interleukin-1 processing (R-HSA-448706)
  The NLRP3 inflammasome (R-HSA-844456)
  NOD1/2 Signaling Pathway (R-HSA-168638)

Molecular Interaction Atlas (MIA) of This DTT

4 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
AC-201	DMB0TNL	Type-2 diabetes	5A11	Phase 2	[2]
Belnacasan	DM2Q50G	Epilepsy	8A60-8A68	Phase 2	[1]
Nivocasan	DMUX8JZ	Fibrosis	GA14-GC01	Phase 2	[3]
PRALNACASAN	DM73UTG	Rheumatoid arthritis	FA20	Phase 2	[4]

2 Patented Agent(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Ac-YVAD-cmk	DMA1RVN	Allergic contact dermatitis	EK00	Patented	[5]
Ac-YVAD-FMK	DM7K256	Allergic contact dermatitis	EK00	Patented	[5]

3 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
L-709049	DMQZW6D	N. A.	N. A.	Terminated	[6]
SDZ-224-015	DMY1KE8	Rheumatoid arthritis	FA20	Terminated	[7]
VE-16084	DMHG70W	Rheumatoid arthritis	FA20	Terminated	[8]

5 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
M826	DM9NPE4	Discovery agent	N.A.	Investigative	[9]
YVAD	DM24LNB	Discovery agent	N.A.	Investigative	[10]
Z-VAD-CHO	DMCE8K1	Discovery agent	N.A.	Investigative	[11]
Z-YVAD-CHO	DM0TP2R	Discovery agent	N.A.	Investigative	[11]
Z-YVAD-FMK	DMFTBPI	Discovery agent	N.A.	Investigative	[12]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Rheumatoid arthritis	FA20	Synovial tissue	1.73E-01	0.68	0.61

References

• [1] (S)-1-((S)-2-{[1-(4-amino-3-chloro-phenyl)-methanoyl]-amino}-3,3-dimethyl-butanoyl)-pyrrolidine-2-carboxylic acid ((2R,3S)-2-ethoxy-5-oxo-tetrahydr... J Pharmacol Exp Ther. 2007 May;321(2):509-16.
• [2] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [3] Combined effects of an antioxidant and caspase inhibitor on the reversal of hepatic fibrosis in rats. Apoptosis. 2013 Dec;18(12):1481-91.
• [4] Pralnacasan, an inhibitor of interleukin-1beta converting enzyme, reduces joint damage in two murine models of osteoarthritis. Osteoarthritis Cartilage. 2003 Oct;11(10):738-46.
• [5] Caspase inhibitors: a review of recently patented compounds (2013-2015).Expert Opin Ther Pat. 2018 Jan;28(1):47-59.
• [6] Succinic acid amides as P2-P3 replacements for inhibitors of interleukin-1beta converting enzyme (ICE or caspase 1). Bioorg Med Chem Lett. 2010 Sep 1;20(17):5184-90.
• [7] Reduction of inflammation and pyrexia in the rat by oral administration of SDZ 224-015, an inhibitor of the interleukin-1 beta converting enzyme. Br J Pharmacol. 1995 Jun;115(4):601-6.
• [8] Interleukin-1 beta converting enzyme inhibition blocks progression of type II collagen-induced arthritis in mice. Cytokine. 1996 May;8(5):377-86.
• [9] Novel pyrazinone mono-amides as potent and reversible caspase-3 inhibitors. Bioorg Med Chem Lett. 2005 Feb 15;15(4):1173-80.
• [10] Mice deficient in interleukin-1beta converting enzyme resist anorexia induced by central lipopolysaccharide. Am J Physiol. 1999 Nov;277(5 Pt 2):R1435-43.
• [11] Tethering identifies fragment that yields potent inhibitors of human caspase-1. Bioorg Med Chem Lett. 2006 Feb;16(3):559-62.
• [12] Different molecular events account for butyrate-induced apoptosis in two human colon cancer cell lines. J Nutr. 2002 Jul;132(7):1812-8.