CALIFIA BIO
Califia Bio has been awarded a $218,000 NIH SBIR grant to identify drug-like small molecule mimetics of GRK2ct, which act by modulation of G-protein signaling, for treatment of heart failure. This work will be conducted in collaboration with Dr. Alan Smrcka's research group at the University of Rochester.
Heart Failure. Heart disease is the leading cause of death in the U.S. Heart failure is estimated to be a $2 billion drug market for which there is great unmet therapeutic need. There are approximately 5.7 million heart failure patients in the US, and 670,000 new cases per year. In end stage heart failure, only one half of patients will survive one year, at this stage of the disease the only proven treatment is heart transplant. Unfortunately, in the US, only approximately 2000 patients per year receive new hearts. Califia Bio is engaged in two projects related to heart failure.
G-Protein Signaling: Alan Smrcka and coworkers at the University of Rochester have identified peptide and small molecule modulators of G protein signaling.1 These modulators interact at the Gα/βγ interface. Califia Bio is participating with Professor Smrcka to identify and develop drug-like molecules to modulate Gβγ signaling. G protein receptor kinase 2 (GRK2) also known as β-adrenergic receptor kinase 1 (BARK1) is believed to play a role in heart failure by hyper-activation and ultimate desensitization of the β-adrenergic receptor. GRK2 activity is controlled by Gβγ, which upon GPCR activation is released and recruits GRK2 to the receptor leading to βAR phosphorylation and desensitization. A carboxy-terminal protein fragment of GRK2 acting at the Gα/βγ “hot spot”, blocks this recruitment and enhances βAR function. Burns Blaxall at the URMC has demonstrated that small molecules are capable of interfering with Gβγ signaling and can halt progression of heart failure in calsequestrin cardiac transgenic mice (CSQ) animal models.2 We are collaborating with Dr. Smrcka and Dr. Blaxall to identify drug-like small molecule mimetics of GRK2ct which act by modulation of Gβγ signaling.
Inflammation, Kinase Signalling and Heart Failure: We are collaborating with Dr. Burns Blaxall at URMC to develop inhibitors of key kinases involved in signaling pathways involved in acute heart failure and have early promising data in a murine model of isoproterenol induced heart failure.
1 Bonacci, T.M., Mathews, J.L., Yuan, C., Lehmann, D., Malik S., Wu, D., Font, J.L., Bidlack, J.M. and Smrcka, A.V. Differential Targeting of Gbg-Subunit Signaling wth Small Molecules. Science 312: 443-446, 2006.
2 Casey LM, Pistner AR, Belmonte SL, Migdalovich D, Stolpnik O, Nwakanma FE, Vorobiof G, Dunaevsky O, Matavel A, Lopes CM, Smrcka AV, Blaxall BC. Small molecule disruption of G beta gamma signaling inhibits the progression of heart failure. Circ Res. 2010 Aug 20;107(4):532-9.
