XL844 ¹
Stage
Phase 1
Status
A phase 1 clinical trial of XL844 in combination with gemcitabine in patients with solid tumors is ongoing.
Studies
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, allowing time for the damage to be repaired. Hence CHK1 and CHK2 may reduce 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 by a wide variety of chemotherapeutic agents and radiation in in vitro assays. XL844 has good pharmacokinetic properties and oral bioavailability, and in in vivo tumor models increases the efficacy of chemotherapeutic agents without increasing systemic toxicity.
Additional preclinical data were presented at the 2007 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics in October 2007:
- An analysis of tumor and normal tissue samples indicates that CHK1 and CHK2 RNA and protein are constitutively overexpressed in a variety of tumor tissues compared with normal tissues.
- In vitro studies demonstrate that XL844 potently inhibits CH1 and CHK2 and also has activity against VEGFR2, FLT3, FLT4 and PDGFRß.
- Studies in a human carcinoma cell line show that addition of chemotherapeutic agents (cisplatin or SN38, the active metabolite of irinotecan) leads to activation of CHK1, CHK2, and cdc2 (another mediator of cell cycling), resulting in cell cycle arrest. XL844 reduces cdc2 phosphorylation in a dose-dependent manner, leading to cell cycle progression.
- In vivo, administration of XL844 results in durable modulation of cdc2 activity.
- Cell survival assays show that XL844 potentiates the cytotoxic effects of cisplatin; in tumor models, the combination of XL844 and irinotecan produces a transient but significant inhibition of tumor growth.
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.
Footnotes:
1 Pursuant to a product development and commercialization agreement between Exelixis and GlaxoSmithKline, GlaxoSmithKline has the option, after completion of proof-of-concept by Exelixis, to elect to develop up to three compounds in the Exelixis pipeline including XL820, XL184, XL844, XL281 and XL228.
