JUPITER, Fla.—A joint study between scientists from TheScripps Research Institute and Harvard University's Dana-Farber CancerInstitute has led to the discovery and establishment of a new class ofanti-diabetic compound that targets a specific molecular switch. The discoverycould lead to the eventual development of anti-diabetic therapeutics withminimal adverse side effects compared to the issues faced by currentlyavailable anti-diabetic drugs.
The study was led by Patrick R. Griffin, professor and chairof the department of Molecular Therapeutics at Scripps Florida; BruceSpiegelman, professor of cell biology at the Dana-Farber Cancer Institute; andTheodore Kamenecka, associate scientific director of medicinal chemistry atScripps Florida. It was published Sept. 4 in Nature.
The compound detailed in the study is known as SR1664, andthe study itself follows research the authors published last year in Nature (Volume 466, Issue 7305) suggesting that anobesity-linked mechanism might be involved in the development ofinsulin-resistance. Their research led the authors to find disruptions invarious genes when the protein PPARg undergoes phosphorylationby the kinase Cdk5, which is an enzyme known to be involved in severalimportant sensory pathways.
The latest study confirms that blocking Cdk5's action onPPARG is a workable approach for developing therapeutic anti-diabetic agents.The SR1664 compound is a binder to the nuclear receptor PPARG, but it doesn'tactivate gene transcription via the receptor's usual mechanism.
"In this study, we demonstrate that we have discovered novelcompounds that work effectively through a unique mechanism of action on awell-validated clinical target for diabetes," said Griffin in a press release."This unique mechanism of action appears to significantly limit side effectsassociated with marketed drugs. This study is a great example ofinterdisciplinary, inter-institutional collaboration with chemistry,biochemistry, structural biology and pharmacology."
Griffin noted that there will be some difficulty in terms ofassessing the side effects of new compounds such as SR1664, but at the sametime, noticeably fewer of the major well-documented side effects seen inanti-diabetic drugs, such as weigh gain or increased plasma volume, weredemonstrated in mice treated with SR1664 in comparison to those treated withAvandia, a current anti-diabetic drug scheduled to be removed due to side effect concerns. While both sets of mice demonstrated improved blood sugar levels,those that received Avandia also displayed weight gain and increased fluidretention within a few days of the start of the treatment regimen. Incomparison, the mice treated with SR1664 showed neither weight gain norincreased fluid retention. In cell culture studies, SR1664 did not appear tohave much effect on bone formation or cause increased fat generation in bonecells, two other side effects of currently available therapies such as Avandia.
S1664 will most likely not be developed as a drug, but itcan serve as a molecular scaffolding for developing compounds with thepotential to treat diabetes.
"With data in hand showing that our compounds are asefficacious as the currently marketed PPARG modulators, while demonstrating asignificant improvement of side effects in limited studies, we are nowadvancing newer compounds with improved pharmaceutical properties intoadditional studies," Griffin noted.
"It appears that we may have an opportunity to developentire new classes of drugs for diabetes and perhaps other metabolicdisorders," said Spiegelman.
The title of the study, which was supported by the NationalInstitutes of Health, is "Anti-Diabetic Actions of a Non-Agonist PPARG LigandBlocking Cdk5-Mediated Phosphorylation." The first authors of the study, listedas equal contributors, are Jang Hyun Choi and Alexander S. Banks of theDana-Farber Cancer Institute and Theodore M. Kamenecka and Scott A. Busby ofthe Scripps Research Institute. Other authors include Michael J. Chalmers,Naresh Kumar, Dana S. Kuruvilla, Youseung Shin, Yuanjun He, David Marciano andMichael D. Cameron of Scripps Research Institute; Dina Laznik of theDana-Farber Cancer Institute; Michael J. Jurczak and Gerald I. Shulman of theHoward Hughes Medical Institute; Stephan C. Schurer and Dusica Vidovic of theUniversity of Miami; and John B. Bruning of Texas A&M University.
SOURCE: Scripps Research Institute press release
