Back to products

Browse products

Approved anticancer agents

Anticancer agents in trials

Anticancer molecular libraries

MedKoo product information:

VX-765

VX-765 is designed to inhibit Caspase, which is an enzyme that controls the generation of two cytokines, IL-1b and IL-18. VX-765 has been shown to inhibit acute seizures in preclinical models. In addition, VX-765 has shown activity in preclinical models of chronic epilepsy. VX-765 had been dosed in over 100 patients in phase-I and phase-IIa clinical trials relating to other diseases, including a 28-day phase-IIa clinical trial in patients with psoriasis. It has completed the treatment phase of a phase-IIa clinical trial of VX-765 that enrolled approximately 75 patients with treatment-resistant epilepsy. The double-blind, randomized, placebo-controlled clinical trial was designed to evaluate the safety, tolerability and clinical activity of VX-765.

Current developer:    Vertex Pharmaceuticals  

VX-765 is a novel Caspase-1 inhibitor being investigated for the treatment of epilepsy., currently  being developed by Vertex.  VX-765 is an orally-absorbed pro-drug of VRT-043198, a potent and selective inhibitor of ICE/caspase-1 sub-family caspases. VRT-043198 exhibits 100-10,000-fold selectivity against other caspase-3 and -6-9.  In cultures of peripheral blood mononuclear cells and whole blood from healthy subjects stimulated with bacterial products, VRT-043198 inhibited the release of Interleukin (IL)-1beta and IL-18, but had little effect on the release of several other cytokines, including IL-1alpha, tumor necrosis factor-alpha, IL-6 and IL-8. In contrast, VRT-043198 had little or no demonstrable activity in cellular models of apoptosis and did not affect the proliferation of activated primary T-cells or T-cell lines. VX-765 was efficiently converted to VRT-043198 when administered orally to mice and inhibited LPS-induced cytokine secretion. In addition, VX-765 reduced disease severity and the expression of inflammatory mediators in models of rheumatoid arthritis and skin inflammation. 

According to Vertex's website, VX-765 has been shown to inhibit acute seizures in preclinical models of acute epilepsy and has shown activity in preclinical models of chronic epilepsy that do not respond to standard anti-epileptic drugs. Vertex recently initiated a Phase 2 proof-of-concept clinical trial of VX-765 in patients with epilepsy, which could result in interim clinical data being available as early as the second half of 2010. The Phase 2 trial for VX-765 is expected to enroll approximately 75 patients with treatment-resistant epilepsy.

 1. Boxer, Matthew B.; Quinn, Amy M.; Shen, Min; Jadhav, Ajit; Leister, William; Simeonov, Anton; Auld, Douglas S.; Thomas, Craig J. A Highly Potent and Selective Caspase 1 Inhibitor that Utilizes a Key 3-Cyanopropanoic Acid Moiety. ChemMedChem (2010), 5(5), 730-738. 

2. Eda, Hiroyuki. Therapeutic potential for caspase inhibitors: Present and future. Design of Caspase Inhibitors as Potential Clinical Agents (2009), 251-287. 

3. Spada, Alfred P. Combination therapy for the treatment of liver diseases. U.S. Pat. Appl. Publ. (2008), 38 pp. CODEN: USXXCO US 2008207605 A1 20080828 CAN 149:299832 AN 2008:1045991

4. Ravizza, Teresa; Noe, Francesco; Zardoni, Daniela; Vaghi, Valentina; Sifringer, Marco; Vezzani, Annamaria. Interleukin Converting Enzyme inhibition impairs kindling epileptogenesis in rats by blocking astrocytic IL-1 production. Neurobiology of Disease (2008), 31(3), 327-333. CODEN: NUDIEM ISSN:0969-9961. CAN 150:160017 AN 2008:1001086

5. Tanoury, Gerald J.; Chen, Minzhang; Dong, Yong; Forslund, Raymond E.; Magdziak, Derek. Development of a Novel Pd-Catalyzed N-Acyl Vinylogous Carbamate Synthesis for the Key Intermediate of ICE Inhibitor VX-765. Organic Letters (2008), 10(2), 185-188. CODEN: ORLEF7 ISSN:1523-7060. CAN 148:239482 AN 2007:1430767

6. Wannamaker, Woods; Davies, Robert; Namchuk, Mark; Pollard, John; Ford, Pamella; Ku, George; Decker, Caroline; Charifson, Paul; Weber, Peter; Germann, Ursula A.; Kuida, Keisuke; Randle, John C. R. (S)-1-((S)-2-{[1-(4-Amino-3-chlorophenyl)methanoyl]amino}-3,3-dimethylbutanoyl)-pyrrolidine-2-carboxylic acid ((2R,3S)-2-ethoxy-5-oxo-tetrahydro-furan-3-yl)amide (VX-765), an orally available selective interleukin (IL)-converting enzyme/caspase-1 inhibitor, exhibits potent anti-inflammatory activities by inhibiting the release of IL-1 and IL-18. Journal of Pharmacology and Experimental Therapeutics (2007), 321(2), 509-516. CODEN: JPETAB ISSN:0022-3565. CAN 147:133453 AN 2007:513268

7. Cornelis, Sigrid; Kersse, Kristof; Festjens, Nele; Lamkanfi, Mohamed; Vandenabeele, Peter. Inflammatory caspases: targets for novel therapies. Current Pharmaceutical Design (2007), 13(4), 367-385. CODEN: CPDEFP ISSN:1381-6128. CAN 146:414125 AN 2007:388645

8. Ravizza, Teresa; Lucas, Sian-Marie; Balosso, Silvia; Bernardino, Liliana; Ku, George; Noe, Francesco; Malva, Joao; Randle, John C. R.; Allan, Stuart; Vezzani, Annamaria. Inactivation of caspase-1 in rodent brain: a novel anticonvulsive strategy. Epilepsia (2006), 47(7), 1160-1168. CODEN: EPILAK ISSN:0013-9580. CAN 145:465566 AN 2006:953147

9. Linton, Steven D. Caspase inhibitors: a pharmaceutical industry perspective. Current Topics in Medicinal Chemistry (Sharjah, United Arab Emirates) (2005), 5(16), 1697-1716. CODEN: CTMCCL ISSN:1568-0266. CAN 144:266489 AN 2006:270630

10. Stack, Jeffrey H.; Beaumont, Kevin; Larsen, Paul D.; Straley, Kimberly S.; Henkel, Greg W.; Randle, John C. R.; Hoffman, Hal M. IL-Converting Enzyme/Caspase-1 Inhibitor VX-765 Blocks the Hypersensitive Response to an Inflammatory Stimulus in Monocytes from Familial Cold Autoinflammatory Syndrome Patients. Journal of Immunology (2005), 175(4), 2630-2634. CODEN: JOIMA3 ISSN:0022-1767. CAN 143:241593 AN 2005:700924

11. Shafer, Lisa L. Techniques to treat neurological disorders by attenuating the production of proinflammatory mediators. U.S. Pat. Appl. Publ. (2005), 21 pp. CODEN: USXXCO US 2005095246 A1 20050505 CAN 142:451800 AN 2005:394529

12. Randle, John C. R. Orally-active ICE inhibitors for the treatment of inflammatory and autoimmune diseases. Abstracts of Papers, 228th ACS National Meeting, Philadelphia, PA, United States, August 22-26, 2004 (2004), MEDI-200. CODEN: 69FTZ8 AN 2004:658064