EPC2407, a new beta-tubulin vascular disrupting agent with potent apoptosis and cell growth inhibition

Abstract

14043 Background: Compounds which bind to colchicine-like sites of microtubules have contributed greatly to the armamentarium of cancer therapies. But new modes of administration of taxanes and potent new vascular disruption agent molecules such as combretastatin continue to challenge drug development for ways to improve the therapeutic index in this important class. EPC2407 is a novel 4-aryl chromene of nM anti-tumor potency; it is crossing the translational bridge based on an array of preclinical anti-tumor pharmacology and supported by multiple toxicology trials which included drug exposure data. Methods: Vascular disrupting agents demand careful preclinical workup. What we have done is summarized in the table below. This data is from cellular metabolic, cell proliferation, vascular endothelial, in vivo tumor, and animal toxicokinetic and safety studies. Results: Please see table below of the preclinical experiments. Conclusions: A Phase I clinical trial has been designed and initiated to replicate the safety margin shown by the analysis of preclinical drug exposure data. The critical safety issue for human dosing was the dose exposure which might produce the well known ECG abnormality of delayed repolarization or prolonged QTc. A dose related QTc effect was demonstrated in cynomolgus monkeys after a 2 min infusion which achieved acute plasma exposures higher than 3836 nM. These effects were dose related and persisted only through 4 short half-lives of the parent compound. Initial human analysis fails to show any prolongation of the QTc. [JW1] [JW1]THE END HERE, all else was draft. [Table: see text] No significant financial relationships to disclose.