Dr. Anjali Pandey, Ph.D. has been Senior Vice President of Medicinal Chemistry & Chemical Development at Portola Pharmaceuticals, Inc. since August 5, 2015. Dr. Pandey served as a Vice President of Chemistry at Portola Pharmaceuticals, Inc since April 2006 until August 5, 2015. Dr. Pandey served as Vice President of Medical Chemistry at Portola Pharmaceuticals, Inc. Ms. Pandey joined Portola in 2003. Ms. Pandey served as the Director of Chemistry at Millennium. She also
|AML FIGHTERPandey, shown in her lab at Millennium, helped develop an acute myelogenous leukemia agent.MILLENNIUM PHARMACEUTICALS PHOTO|
Anjali Pandey, director of cardiovascular chemistry at Millennium Pharmaceuticals, South San Francisco, reported on CT53518 (also known as MLN518), a potent, orally available inhibitor of the enzyme FLT-3. The drug is a potential therapy for acute myelogenous leukemia (AML), a form of cancer in which abnormal white blood cells accumulate in the blood and bone marrow, resulting in hemorrhage, fatigue, and other symptoms.
FLT-3 is a receptor tyrosine kinase (a tyrosine kinase found in cell membranes) and a member of the platelet-derived growth factor receptor (PDGFR) family of enzymes. These cell-signaling enzymes have been implicated in a variety of cancers and other diseases and are a major focus of current drug discovery efforts.
"Kinase inhibition represents a novel mechanism-based approach to selectively block cell-signaling pathways," Pandey said. "This strategy has been validated recently by the introduction of the Bcr-Abl kinase inhibitor Gleevec for chronic myeloid leukemia" (CML). Gleevec is a Novartis drug that prevents activation of Bcr-Abl, the abnormal nonreceptor tyrosine kinase that causes CML.
More than one-quarter of AML patients have internal duplications in FLT-3 that cause the enzyme to be activated inappropriately and that are associated with significant increases in relapse and mortality rates. Inhibiting FLT-3 could help ameliorate AML symptoms in such patients.
Pandey and coworkers at Millennium began their project by identifying a quinazoline class of compounds as leads for FLT-3 inhibitors in a high-throughput screening procedure. Pandey noted that, in the past, the quinazolines have been a prolific source of tyrosine kinase inhibitors, such as ZD1839 (Iressa) and OSI-774 (Tarceva), which are in Phase III and Phase II clinical trials for cancer, respectively. ZD1839 is an AstraZeneca drug; OSI-774 is being codeveloped by OSI Pharmaceuticals, Genentech, and Roche.
The original quinazolines identified by Pandey and coworkers had instability, potency, and aqueous solubility problems. So the researchers synthesized a range of variants, analyzed SAR data on these compounds, and further modified their structures to zero in on agents with optimal in vitro potency and physicochemical properties. They narrowed the field to four compounds, tested them in animals, and chose CT53518 (MLN518) as a clinical candidate for further characterization.
The group found that the drug delayed disease progression in a mouse model of FLT-3-associated AML and caused apoptosis (cell death) in a human AML cell line. "We have done 28-day toxicological tests in rat and dog, and it looks pretty good," Pandey said--except for some slight suppression of bone marrow, which she and her coworkers had expected. "Phase I clinical trials in AML patients have been initiated," she said, "and we are very hopeful" that results will continue to be favorable.