title: LC/MS characterization of impurities and degradation products of a potent antitumor peptidic dimer, CU201.
abstract: Compound CU201 [SUIM-(d-Arg-Arg-Pro-Hyp-Gly-Igl-Ser-d-Igl-Oic-Arg)(2), where SUIM=suberimidyl; Hyp=trans-4-hydroxyproline; Igl=alpha-(2-indanyl)-glycine; Oic=octahydroindole-2-carboxylic acid], is a dimeric analog of the potent bradykinin antagonist peptide B9430. It blocks the G(alphaq,11) signal of the heterotrimeric G proteins, stimulates c-Jun kinases, and induces apoptosis in lung cancer cells with neuroendocrine features. CU201 shows potent inhibition for small-cell lung cancer cells in vitro (ED(50)=0.15microM), as well as for small-cell lung cancer SHP-77 tumor growth in vivo. An HPLC method was developed, as part of a study supported by the National Cancer Institute's (NCI's) Rapid Access to Interventional Development (RAID) program, to assess the purity and stability of CU201. Impurities and degradation products were characterized by LC/MS. The identity of a major impurity, with 1 mass unit different from CU201, was confirmed by high resolution LC/MS and the investigation of model compounds. Susceptible linkages in the peptide chains were revealed by the degradation study.
authors.affiliation: SRI International, 333 Ravenswood Avenue, Menlo Park, CA 94025, USA. jennie.wang@sri.com
authors.forename: Jennie
authors.initials: J
authors.lastname: Wang
authors.forename: Vidhya
authors.initials: V
authors.lastname: Krishnamoorthi
authors.forename: Euphemia
authors.initials: E
authors.lastname: Wang
authors.forename: Chun
authors.initials: C
authors.lastname: Yang
authors.forename: Diego
authors.initials: D
authors.lastname: Baptista
authors.forename: Xiaogang
authors.initials: X
authors.lastname: Wu
authors.forename: Mingtao
authors.initials: M
authors.lastname: Liu
authors.forename: Michael
authors.initials: M
authors.lastname: Gardner
authors.forename: Phyllis
authors.initials: P
authors.lastname: Elkins
authors.forename: John
authors.initials: J
authors.lastname: Hines
authors.forename: Paul
authors.initials: P
authors.lastname: Liu
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry*; D002851:Chromatography, High Pressure Liquid; D056148:Chromatography, Reverse-Phase; D004340:Drug Contamination; D004355:Drug Stability; D006868:Hydrolysis; D013058:Mass Spectrometry; D009842:Oligopeptides / Q000737:chemistry*; D055503:Protein Multimerization
chemical_list: D000970:Antineoplastic Agents; C466459:CU201; D009842:Oligopeptides