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Cryptophycins-309, 249 and other cryptophycin analogs: Preclinical efficacy studies with mouse and human tumors

  • Jian Liang
  • Richard E. Moore
  • Eric D. Moher
  • John E. Munroe
  • Rima S. Al-awar
  • David A. Hay
  • David L. Varie
  • Tony Y. Zhang
  • James A. Aikins
  • Michael J. Martinelli
  • Chuan Shih
  • James E. Ray
  • Lowell L. Gibson
  • Vasu Vasudevan
  • Lisa PolinEmail author
  • Kathryn White
  • Juiwanna Kushner
  • Chiab Simpson
  • Susan Pugh
  • Thomas H. Corbett
Article

Summary

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 × 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.

Key words

cryptophycin glycinate anti-tumor preclinical mice 

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Copyright information

© Springer Science + Business Media, Inc. 2005

Authors and Affiliations

  • Jian Liang
    • 1
  • Richard E. Moore
    • 2
  • Eric D. Moher
    • 3
  • John E. Munroe
    • 3
  • Rima S. Al-awar
    • 3
  • David A. Hay
    • 3
  • David L. Varie
    • 3
  • Tony Y. Zhang
    • 3
  • James A. Aikins
    • 3
  • Michael J. Martinelli
    • 3
  • Chuan Shih
    • 3
  • James E. Ray
    • 3
  • Lowell L. Gibson
    • 3
  • Vasu Vasudevan
    • 3
  • Lisa Polin
    • 4
    • 5
    Email author
  • Kathryn White
    • 4
  • Juiwanna Kushner
    • 4
  • Chiab Simpson
    • 4
  • Susan Pugh
    • 4
  • Thomas H. Corbett
    • 4
  1. 1.Department of Molecular Biosciences & BioengineeringUniversity of Hawaii at ManoaHonolulu
  2. 2.Department of ChemistryUniversity of Hawaii at ManoaHonolulu
  3. 3.Lilly Research Laboratories, Eli Lilly and CompanyLilly Corporate CenterIndianapolis
  4. 4.Karmanos Cancer InstituteWayne State University School of MedicineDetroit
  5. 5.Department of Internal Medicine, Karmanos Cancer Institute-PrentisWayne State University School of MedicineDetroit

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