CEP-18770 (Delanzomib)

Delanzomib(CEP-18770) is a novel orally-active inhibitor of the chymotrypsin-like activity of the proteasome that down-modulates the nuclear factor-kappaB (NF-kappaB) activity.IC50 Value: 3.8 nM [1]Target: proteasomein vitro: CEP-18770 and bortezomib showed comparable potency against chymotrypsin-like proteasome activity, cellular inhibitory activity (IC50) values of 3.8 (± 1.0) nM and 3.8 (± 0.4) nM, respectively, CEP-18770 had a 2- to 11-fold lower cytotoxic potency compared with bortezomib against solid tumor cell lines, comparable potency against 2 hematologic tumor cell lines, and a similar spectrum of antiproliferative activity with IC50 values for both compounds of less than 35 nM [1].in vivo: in MM xenograft models, the addition of CEP-18770 IV to melphalan completely prevented the growth of both melphalan-sensitive and melphalan-resistant tumours. The combination of CEP-18770 IV and bortezomib induced complete regression of bortezomib-sensitive tumours and markedly delayed progression of bortezomib-resistant tumours compared to treatment with either agent alone [2]. Age matched MRL/lpr or NZBWF1 mice with established SLE or LN, respectively, were treated with delanzomib either 3 mg/kg once or twice weekly intravenously or orally at 10 mg/kg [3]. Toxicity: CEP-18770 showed a favourable safety profile with lack of neurotoxicity and linear plasma PK. The definition of the optimal biological dose and schedule of treatment is actively pursued because of the high incidence of skin toxicity of the twice a week schedule [4].Clinical trial: CEP-18770 in Combination With Lenalidomide and Dexamethasone in Relapsed or Refractory Multiple Myeloma. Phase1/2

Signaling Pathways >> Metabolic Enzyme/Protease >> Proteasome

Research Areas >> Cancer

[1]. Piva R, et al. CEP-18770: A novel, orally active proteasome inhibitor with a tumor-selective pharmacologic profile competitive with bortezomib. Blood. 2008 Mar 1;111(5):2765-75.

[2]. Sanchez E, et al. The proteasome inhibitor CEP-18770 enhances the anti-myeloma activity of bortezomib and melphalan. Br J Haematol. 2010 Feb;148(4):569-81.

[3]. Seavey MM, et al. Novel, orally active, proteasome inhibitor, delanzomib (CEP-18770), ameliorates disease symptoms and glomerulonephritis in two preclinical mouse models of SLE. Int Immunopharmacol. 2012 Jan;12(1):257-70.

[4]. Gallerani E, et al. A first in human phase I study of the proteasome inhibitor CEP-18770 in patients with advanced solid tumours and multiple myeloma. Eur J Cancer. 2013 Jan;49(2):290-6.

MG-132 | Celastrol | ONX-0914 (PR-957) | Pepstatin | Epoxomicin | Ixazomib (MLN2238) | Calpain Inhibitor I | Oprozomib (ONX 0912) | PD150606 | RA190 | Capzimin | Gabexate mesylate | PI 1840 | VR23 | PD 151746