Title: “Discovery of AZD5305, a next generation, highly selective PARP1 inhibitor and trapper”
By Jeffrey Johannes
Organized by the Medicinal Chemistry Section
of the Northeastern Section, American Chemical Society (NESACS)
Thursday – January 20th, 2022
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Abstract: Poly ADP-ribose polymerase (PARP) inhibitors have demonstrated clinical effectiveness in the treatment of homologous recombination deficient tumors; however, hematological and other toxicities have limited their use as a class of agents, both as monotherapy and as combination with already poorly tolerated chemotherapies. Recent literature has suggested that inhibition of PARP2, a feature shared by all the current clinical PARP inhibitors, is not required for efficacy and may in fact be associated with hematological effects. These observations led to our hypothesis that a highly selective and potent PARP1 inhibitor and trapper would retain efficacy while improving therapeutic index, thus expanding clinical combinations options. Our work in this area culminated in the delivery of AZD5305, a next-generation PARP1 clinical candidate that is a highly potent inhibitor of PARP1 with significant PARP1-DNA trapping activity, no PARP2-activity, and lacks binding to any other members of the PARP family.
Biography: Dr. Jeffrey W. Johannes grew up in Puyallup, Washington, U.S.A., a small city south of Seattle. For his undergraduate studies, he moved to Claremont, California to attend Harvey Mudd College, receiving a Bachelor of Science degree in chemistry in 1999 while working on synthetic transformations of fullerene C60 with professor Philip Myhre. He then joined the lab of Professor Yoshito Kishi at Harvard University to work in the field of natural products synthesis. Following his work on the total synthesis of gymnodimine, he received a Ph.D. in 2005. After staying in Professor Kishi’s lab for an additional year as a post-doctoral fellow, he then joined AstraZeneca in 2006. Since then, Jeff has worked in the oncology medicinal chemistry group in Waltham, MA on a number of diverse oncology targets, spanning both the lead generation and lead optimization phases of drug discovery.
Symposium Organizing Committee: Brian Aquila, Mark Ashwell, Scott Edmondson, Dan Elbaum, Jeremy Green, Paul Greenspan, Adrian Hobson, Blaise Lippa, Lisa Marcaurelle, Min Lu, Kap-Sun Yeung, Andrew Scholte, Mala Gopalsamy, Raj (SB) Rajur (Chair)