PALO ALTO, Calif., April 5, 2011 /PRNewswire/ -- Telik, Inc. (Nasdaq: TELK) today presented data at the 102nd American Association for Cancer Research (AACR) Annual Meeting in Orlando, Florida on a group of second generation analogs of ezatiostat, the most clinically advanced product in development at Telik. Ezatiostat is the first inhibitor of glutathione-S-transferase P1-1 (GST P-1), a validated enzyme target in Myelodysplastic Syndrome (MDS), to successfully complete a Phase 2 clinical trial. The efficacy and tolerability observed with ezatiostat in several Phase 1 and Phase 2 clinical trials supported the initiation of the analog program to identify potential follow-on drug candidates. The structure-activity relationships for the most compelling of these analogs are presented in the AACR poster, entitled Synthesis and Biochemical Characterization of Novel Analogs of Ezatiostat Hydrochloride (TELINTRA®, TLK199) by Danying Cai et al. A copy of the poster will be available on the Telik website at www.telik.com.
A series of diacid ezatiostat analogs bearing different substituents on the cysteinyl sulfur were synthesized using computer aided drug design and TRAP®, a proprietary drug discovery technology, to improve the inhibitory potency and selectivity for the target enzyme GST P1-1. Substitutions resulted in a 30- to 130-fold improvement in in vitro potency against GST P1-1 and 3- to 10-fold higher selectivity relative to other isoforms.
The analogs exhibited potent binding and inhibition of the drug target, GST P1-1, leading to activation of the signaling molecule Jun kinase. Like ezatiostat, the analogs induced programmed cell death, or apoptosis, of human leukemia cells as well as the growth and differentiation of normal blood stem cells, leading to the acceleration of recovery of neutrophil levels in preclinical models of chemotherapy-induced neutropenia. Further investigation of the most potent and selective analogs in biochemical and cellular assays is underway to assess their potential as clinical development candidates for the treatment of hematologic malignancies.
Select ezatiostat analogs were evaluated for toxicity as well as for acceleration of recovery of neutrophil levels in a standard preclinical model of 5-fluorouracil chemotherapy-induced neutropenia. The compounds were well-tolerated when administered at doses up to 200 mg/kg and, like ezatiostat, led to a significantly accelerated recovery in the 5-FU-induced neutropenia model.
"We are pleased to report new data on novel ezatiostat analogs, which augments the substantial scientific foundation and intellectual property estate of this program", stated James Keck Ph.D., Vice President of Biology Research. "The availability of the analogs will help to further our understanding of ezatiostat treatment for MDS as well as the role of GST P1-1 in the development and progression of MDS."
Ezatiostat treatment has been shown to cause a clinically significant and sustained reduction in red-blood-cell transfusions, transfusion independence, and multilineage hematologic improvement responses in patients with MDS. Positive results of a Phase 2 multicenter study that evaluated ezatiostat administered on two extended dose schedules in 89 heavily pre-treated patients with low to intermediate-1 risk MDS were recently reported in the Proceedings of the American Society of Hematology Annual Meeting 2010; 116: Abstract 2910. Phase 2 Randomized Multicenter Study of Extended Dosing Schedules of Oral Ezatiostat HCl (Telintra), a Glutathione Analog Prodrug GST P1-1 Inhibitor in Low to Intermediate-1 Risk Myelodysplastic Syndrome: Raza A, Galili N, Smith SE, Godwin J, Boccia RV, Myint H, et al.
Background on MDS and TELINTRA
The myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis (blood cell production) involving one or more cell lineages (red blood cells, white blood cells or platelets) and a variable risk of transformation to acute myeloid leukemia (AML). MDS becomes more common with age. It is estimated that MDS affects approximately 300,000 people worldwide. According to the American Cancer Society, 10,000–20,000 new cases of MDS are diagnosed each year in the United States, with survival rates ranging from six months to six years. MDS patients often require blood transfusions to manage their disease.
There remains a critical need for effective, well tolerated therapies for MDS. Telintra has a novel mechanism of action that inhibits an enzyme called glutathione S-transferase P1-1, which leads to activation of Jun kinase, a key regulator of cellular growth and differentiation of blood precursor cells. Telintra has been shown to stimulate normal multilineage differentiation of blood stem cell precursors and induce cancer cell death, or apoptosis, in human leukemia cell lines. Additional information about Telintra is available at www.telik.com.
About Telik, Inc.
Telik, Inc. of Palo Alto, CA, is a clinical stage drug development company focused on discovering and developing small molecule drugs to treat cancer. The company's most advanced drug candidate is Telintra®, a modified glutathione analog intended for the treatment of hematologic disorders including myelodysplastic syndrome; followed by Telcyta®, a cancer activated prodrug for the treatment of a variety of cancers. Telik's product candidates were discovered using its proprietary drug discovery technology, TRAP®, which enables the rapid and efficient discovery of small molecule drug candidates.
This press release contains "forward looking" statements regarding the future development of Telintra and its analogs, the effectiveness of Telintra in treating MDS, whether Telintra treatment results in hematologic improvement in patients with MDS or offers an alternative to RBC blood transfusions; and the use of Telcyta for the treatment of cancer. These forward looking statements are based upon Telik's current expectations and there are important factors that could cause actual results to differ materially from those indicated by these forward-looking statements. Detailed information regarding factors that may cause actual results to differ materially from the results expressed or implied by statements in this press release may be found in Telik's periodic filings with the Securities and Exchange Commission, including the factors described in the section entitled "Risk Factors" in its annual report on Form 10-K for the year ending December 31, 2010. Telik does not undertake any obligation to update forward looking statements contained in this press release.
Telik, the Telik logo, TELINTRA, TELCYTA and TRAP are trademarks or registered trademarks of Telik, Inc.
SOURCE Telik, Inc.