title: Cryptophycins-309, 249 and other cryptophycin analogs: preclinical efficacy studies with mouse and human tumors.
abstract: Cryptophycins-1 and 52 (epoxides) were discovered to have in-vitro and in-vivo antitumor activity in the early 1990s. The chlorohydrins of these, Cryptophycins-8 and 55 (also discovered in the early 1990s) were markedly more active, but could not be formulated as stable solutions. With no method to adequately stabilize the chlorohydrins at the time, Cryptophycin-52 (LY 355073) entered clinical trials, producing only marginal antitumor activity. Since that time, glycinate esters of the hydroxyl group of the chlorohydrins have been synthesized and found to provide stability. Three of the most active were compared herein. Cryptophycin-309 (C-309) is a glycinate ester of the chlorohydrin Cryptophycin-296. The glycinate derivative provided both chemical stability and improved aqueous solubility. After the examination of 81 different Cryptophycin analogs in tumor bearing animals, C-309 has emerged as superior to all others. The following %T/C and Log Kill (LK) values were obtained from a single course of IV treatment (Q2d x 5) against early staged SC transplantable tumors of mouse and human origin: Mam 17/Adr [a pgp (+) MDR tumor]: 0%T/C, 3.2 LK; Mam 16/C/Adr [a pgp (-) MDR tumor]: 0%T/C, 3.3 LK; Mam 16/C: 0%T/C, 3.8 LK; Colon 26: 0%T/C, 2.2 LK; Colon 51: 0%T/C, 2.4 LK; Pancreatic Ductal Adenocarcinoma 02 (Panc 02): 0%T/C, 2.4 LK; Human Colon HCT15 [a pgp (+) MDR tumor]: 0%T/C, 3.3 LK; Human Colon HCT116: 0%T/C, 4.1 LK. One additional analog, Cryptophycin-249 (C-249, the glycinate of Cryptophycin-8), also emerged with efficacy rivaling or superior to C-309. However, there was sufficient material for only a single C-249 trial in which a 4.0 LK was obtained against the multidrug resistant breast adenocarcinoma Mam-16/C/Adr. C-309 and C-249 are being considered as second-generation clinical candidates.
authors.affiliation: Department of Molecular Biosciences & Bioengineering, University of Hawaii at Manoa, Honolulu, HI 96822, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Liang
authors.forename: Richard E
authors.initials: RE
authors.lastname: Moore
authors.forename: Eric D
authors.initials: ED
authors.lastname: Moher
authors.forename: John E
authors.initials: JE
authors.lastname: Munroe
authors.forename: Rima S
authors.initials: RS
authors.lastname: Al-awar
authors.forename: David A
authors.initials: DA
authors.lastname: Hay
authors.forename: David L
authors.initials: DL
authors.lastname: Varie
authors.forename: Tony Y
authors.initials: TY
authors.lastname: Zhang
authors.forename: James A
authors.initials: JA
authors.lastname: Aikins
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Martinelli
authors.forename: Chuan
authors.initials: C
authors.lastname: Shih
authors.forename: James E
authors.initials: JE
authors.lastname: Ray
authors.forename: Lowell L
authors.initials: LL
authors.lastname: Gibson
authors.forename: Vasu
authors.initials: V
authors.lastname: Vasudevan
authors.forename: Lisa
authors.initials: L
authors.lastname: Polin
authors.forename: Kathryn
authors.initials: K
authors.lastname: White
authors.forename: Juiwanna
authors.initials: J
authors.lastname: Kushner
authors.forename: Chiab
authors.initials: C
authors.lastname: Simpson
authors.forename: Susan
authors.initials: S
authors.lastname: Pugh
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Corbett
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D047630:Depsipeptides / Q000737:chemistry / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D004852:Epoxy Compounds / Q000737:chemistry / Q000494:pharmacology*; D004952:Esters; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008813:Mice, Inbred ICR; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D010456:Peptides, Cyclic / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D047630:Depsipeptides; D004852:Epoxy Compounds; D004952:Esters; D010456:Peptides, Cyclic; C504332:cryptophycin 249; C504330:cryptophycin 309; C088419:cryptophycin