December 6, 2018
Insider attacks: Purdue developing new treatment options for millions with autoimmune diseases
WEST LAFAYETTE, Ind. – Living with an autoimmune disease can feel like an insider is attacking your body. An estimated 24 million people in the United States are affected by autoimmune diseases, a group of diseases in which the person’s immune system attacks part of the person’s own body.
Now, Purdue University researchers have developed a series of molecules that may provide more reliable relief with fewer side effects for people with any of several autoimmune diseases. The new molecules overcome difficulties with current drugs in targeting, for purposes of inhibiting, the appropriate form of Janus kinase, which has four forms affecting cell signaling and gene expression.
The new inhibitors may provide relief for people suffering from rheumatoid arthritis, psoriasis, myelofibrosis and other autoimmune diseases with a reduction in side effects compared with current therapies. The research appears in the November edition of the Journal of Medicinal Chemistry.
“Our new molecules fit within the emerging field of therapeutically useful Janus kinase inhibitors that have attracted a lot of attention and excitement within the medicinal chemistry community and the general field of medicine,” said Mark Cushman, a distinguished professor of medicinal chemistry in Purdue’s College of Pharmacy, who leads the research team. “Our compounds contribute a new structural chemotype that is expected to have unique pharmacological properties relative to the other known Janus kinase inhibitors.”
Cushman, a member of the Purdue University Center for Cancer Research, said the new molecules also show potential to allow for more treatment options for people with autoimmune diseases. Abnormalities of the immune system often lead to autoimmune diseases or cancer.
The work aligns with Purdue's Giant Leaps celebration, celebrating the university’s global advancements in health as part of Purdue’s 150th anniversary. This is one of the four themes of the yearlong celebration’s Ideas Festival, designed to showcase Purdue as an intellectual center solving real-world issues.
Researchers filed a patent with the Purdue Office of Technology Commercialization and the technology is available for licensing.
About Purdue Office of Technology Commercialization
The Purdue Office of Technology Commercialization operates one of the most comprehensive technology transfer programs among leading research universities in the U.S. Services provided by this office support the economic development initiatives of Purdue University and benefit the university's academic activities. The office is managed by the Purdue Research Foundation, which received the 2016 Innovation and Economic Prosperity Universities Award for Innovation from the Association of Public and Land-grant Universities. For more information about funding and investment opportunities in startups based on a Purdue innovation, contact the Purdue Foundry at email@example.com. For more information on licensing a Purdue innovation, contact the Office of Technology Commercialization at firstname.lastname@example.org. The Purdue Research Foundation is a private, nonprofit foundation created to advance the mission of Purdue University.
About Purdue University Center for Cancer Research
The Purdue University Center for Cancer Research brings together the best minds from within Purdue University and beyond to study cancers where they start — inside the cell. Using the combined expertise of scientists from disciplines as varied as engineering and veterinary medicine, biology, and chemistry, the Center for Cancer Research promotes discovery into how cancers develop, progress and respond to treatment. The work leads to the advancement of new medicines, early detection and diagnostic methods, more effective treatments, and highly efficient drug delivery systems.
Application of Sequential Palladium Catalysis for the Discovery of Janus Kinase Inhibitors in the Benzo[c]pyrrolo[2,3-h][1,6]naphthyridin-5-one (BPN) Series
Mohamed S. A. Elsayed, Jeffery J. Nielsen, Sungtae Park, Jeongho Park, Qingyang Liu, Chang H. Kim, Yves Pommier, Keli Agama, Philip S. Low, and Mark Cushman
The present account describes the discovery and development of a new benzo[c]pyrrolo[2,3-h][1,6]naphthyridin-5-one (BPN) JAK inhibitory chemotype that has produced selective JAK inhibitors. Sequential palladium chemistry was optimized for the rapid access to a focused library of derivatives to explore the structure–activity relationships of the new scaffold. Several compounds from the series displayed potencies in the low nanomolar range against the four members of the JAK family with various selectivity profiles. Compound 20a, with an azetidine amide side chain, showed the best selectivity for JAK1 kinase vs JAK2, JAK3, and TYK2, with low nanomolar potency (IC50 = 3.4 nM). On the other hand, BPNs 17b and 18 had good general activity against the JAK family with excellent kinome selectivity profiles. Many of the new BPNs inhibited JAK3-mediated STAT-5 phosphorylation, the production of inflammatory cytokines, and the proliferation of primary T cells. Moreover, BPN 17b showed very similar in vivo results to tofacitinib in a rheumatoid arthritis animal model.