Exelixis, Inc., a biotechnology company, has submitted an investigational new drug application (IND) to the US Food and Drug Administration for XL228, a novel anticancer compound designed to inhibit the insulin-like growth factor type-1 receptor (IGF1R), Src and Abl tyrosine kinases. These targets play crucial roles in cancer cell proliferation, survival and metastasis. Importantly, XL228 is a potent inhibitor of the T315I mutant form of the Abl protein, which is associated with resistance to currently approved therapies like Gleevec (imatinib mesylate) and Sprycel (dasatanib). In preclinical studies, administration of XL228 resulted in significant tumour growth inhibition and regression in xenograft tumour models.

"We believe that XL228 is the first compound to advance into the clinic with potent, low-nanomolar activity against both wild-type Abl and the T315I mutant form of Abl that is seen in a significant fraction of chronic myelogenous leukaemia (CML) patients who have become resistant to treatment with Gleevec," said George A. Scangos, president and chief executive officer of Exelixis. "Targeting this mutation, in addition to potently inhibiting wild-type Abl and Src may address the increasing medical needs of CML patients who do not respond or develop resistance to Gleevec or Sprycel and provides us with a potentially accelerated path through clinical development. XL228 is our eighth internally discovered compound to advance to IND filing and the first of three INDs we expect to file this year."

XL228 is a potent inhibitor of several tyrosine kinases implicated in the growth, proliferation and metastasis of cancer cells. The compound inhibits the activity of the insulin-like growth factor type-1 receptor (IGF1R), Src and Abl. Significantly, in preclinical studies XL228 had potent activity against the T315I mutant form of Abl, which is associated with resistance to currently approved therapies. In addition, administration of XL228 resulted in significant tumour growth inhibition and regression in xenograft tumour models. Phase I clinical trials of XL228 are expected to initiate in the fourth quarter of 2006.