Batracylin (NSC 320846)

Overview

Batracylin reached Stage 3 of the NCI pipeline, but was dropped in 1989 because of concern about the interspecies differences in toxicity and potential for variable oral absorption. It was subsequently shown that the interspecies variation in toxicity was consistent with the pattern of metabolism of the compound by N-acetyltransferase (NAT2) to the highly toxic acetylated form, N-acetyl-batracylin. COMPARE analysis suggested a similarity to topo II inhibitors and the compound was found to be a topo II inhibitor, but the inhibition is not dependent on ATP, which indicates a favorable approach for treating hypoxic tumors. The compound is also not a substrate for P-glycoprotein, thus eliminating this mechanism for resistance. With currently available testing to exclude patients based on pretreatment genotyping for the fast-metabolizing NAT2 allele, an orally dosed Phase I clinical trial is proposed.

Basic Chemistry

• Chemical Names: batracylin, Isoindolo[1,2-b]quinazolin-12(10H)-one
• Chemical Structure: isoindoloquinazolinone analog

Preclinical Studies

• in vitro
  • 60 cell screen:
    • With two day exposure, there is an overall GI50 (8 experiments) of 34 micromolar with MOLT-4 leukemia (4 micromolar) and XF-498 CNS (5 micromolar) being the most sensitive lines. With 6 day exposure there is an overall GI50 of 10 micromolar (5 experiements) and the most sensitive lines are HL-60(TB) leukemia (0.2 micromolar) and CC RF-CEM leukemia (1 micromolar).

      dose response | mean graph (GI50)

  • Yeast screen :
    • no significant inhibition of yeast lines with specific mutations in cell cycle genes stage 0
  • other cell based assays
• in vivo
  • invivo efficacy studies
    • Significant activity was seen in the Colon Carcinoma 38 model with an oral dose of 800 mg/kg given Q6H X 4. There was also significant activty in the P388/dox resistant model with an i.p. dose of 75 mg/kg given Q1D X 9
    • Screening data summary reports for individual experiments using the DTP invivo solid tumor and/or toxicity testing models are available below. Comments are based upon the results of individual experiments. Variations in outcome can result from changes in many experimental variables including the drug doses, administration routes, dosing schedules, drug vehicles, tumor models and tumor passage status.

      Colon 38, HT-29-luc-D6 xenograft models

• Pharmaceutical Data
• Pharmacology
• Toxicology

Clinical Studies

• IND
  • filed: October 13, 2006
  • activated: November 20, 2006
• active trials