XL844

Stage

Phase 1

Status

A phase 1 clinical trial of XL844 in combination with gemcitabine in patients with solid tumors is ongoing.

Indications

Advanced Solid Tumors

Principal Targets

Cell cycle regulation: CHK1 and CHK2

CHK1 and CHK2 are kinases that induce cell cycle arrest in response to DNA damaging agents, enabling time for the damage to be repaired. Hence, inhibiting CHK1 and CHK2 may increase the efficacy of cancer therapies that work by inducing DNA damage.

Preclinical Data

XL844 is a potent inhibitor of the checkpoint kinases CHK1 and CHK2, which induce cell cycle arrest in response to a variety of DNA damaging agents. Activation of these checkpoints following DNA damage allows for DNA repair and protects tumor cells from the cytotoxic effects of chemo- and radio-therapy. XL844 abrogates these cell cycle blocks and enhances tumor cell killing in vitro by a wide variety of chemotherapeutic agents and radiation. XL844 has good pharmacokinetic properties and oral bioavailability, and increases the activity of chemotherapeutic agents in tumor models in vivo without increasing systemic toxicity.

Preclinical data published in January 2007 demonstrate that XL844 substantially increases gemcitabine cell killing in multiple in vitro cell models. In vitro assay data show that XL844 abrogates cell cycle arrest induced by gemcitabine and increases DNA damage compared with gemcitabine treatment alone. In vivo, XL844 significantly enhances the extent and duration of gemcitabine-mediated tumor growth inhibition. Based on these data, a phase 1 trial of XL844 in combination with gemcitabine was initiated in patients with advanced malignancies.

Additional preclinical data were presented at the October 2007 AACR-NCI- EORTC International Conference on Molecular Targets and Cancer Therapeutics, demonstrating overexpression of CHK1 and CHK2 in tumors as well as XL844-mediated enhancement of chemotherapeutic tumor cell growth inhibition in vitro and in vivo.

View the abstract and poster

Information on Clinical Trials

Information about ongoing clinical trials of Exelixis' investigational product candidates is available at ClinicalTrials.gov, a service of the U.S. National Institutes of Health. General information about clinical trials and issues related to participating in clinical trials also is available at ClinicalTrials.gov.

Related Publications

For publication information related to this compound, please see the Related Publications page.