2. Academic Validation
  3. New antimitotic agents with activity in multi-drug-resistant cell lines and in vivo efficacy in murine tumor models

New antimitotic agents with activity in multi-drug-resistant cell lines and in vivo efficacy in murine tumor models

  • J Med Chem. 2001 Dec 6;44(25):4416-30. doi: 10.1021/jm010231w.
B G Szczepankiewicz 1,  G Liu,  H S Jae,  A S Tasker,  I W Gunawardana,  T W von Geldern,  S L Gwaltney 2nd,  J R Wu-Wong,  L Gehrke,  W J Chiou,  R B Credo,  J D Alder,  M A Nukkala,  N A Zielinski,  K Jarvis,  K W Mollison,  D J Frost,  J L Bauch,  Y H Hui,  A K Claiborne,  Q Li,  S H Rosenberg
Affiliations

Affiliation

  • 1 Pharmaceutical Products Division, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064, USA. [email protected]
PMID: 11728187 DOI: 10.1021/jm010231w
Abstract

During a screen for compounds that could inhibit cell proliferation, a series of new tubulin-binding compounds was identified with the discovery of oxadiazoline 1 (A-105972). This compound showed good cytotoxic activity against non-multi-drug-resistant and multi-drug-resistant Cancer cell lines, but its utility in vivo was limited by a short half-life. Medicinal chemistry efforts led to the discovery of indolyloxazoline 22g (A-259745), which maintained all of the in vitro activity seen with oxadiazoline 1, but also demonstrated a better pharmacokinetic profile, and dose-dependent in vivo activity. Over a 28 day study, indolyloxazoline 22g increased the life span of tumor-implanted mice by up to a factor of 3 upon oral dosing. This compound, and Others of its structural class, may prove to be useful in the development of new chemotherapeutic agents to treat human cancers.

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