Preclinical characterization of CPL-302-201, a novel, highly potent and selective PI3Kδ inhibitor for the treatment of inflammatory disorders
P. Gunerka, O. Musielak, B. Dymek, D. Zdzalik, M. Zagozda, M. Dziachan, M. Malczyk, A. Bujak, P. Grygielewicz, M. Skupinska, J. Hucz-Kalitowska, K. Dubiel, M. Lamparska-Przybysz, M. Wierczorek, A. Stanczak (Lomianki, Warsaw, Lodz, Poland)
Source: International Congress 2014 – New treatments for cough, asthma, COPD and ILDs
Session: New treatments for cough, asthma, COPD and ILDs
Session type: Poster Discussion
Number: 1505
Disease area: Airway diseases
Abstract Background:PI3Kd is predominantly expressed in hematopoietic cells where it is the key enzyme involved in BCR, TCR and FceR signaling essential for immune response. Inhibition of PI3Kd has been proposed as a new anti-inflammatory therapeutic approach in pulmonary or autoimmune disorders and there is an intense effort to develop selective PI3Kd inhibitors.Materials and methods:Using the knowledge-based drug design we developed a novel PI3Kd inhibitor - CPL-302-201. Its activity among the class I of PI3K lipid kinases and selected protein kinases was assessed by ATP-based enzymatic assay. Additionally, its biological potency and selectivity was evaluated in a number of cell-based models by Western blot.Results:CPL-302-201 inhibits PI3Kd kinase activity at low nanomolar concentrations (IC50 = 6,6 nM) and exhibits outstanding selectivity over a , b and g isoforms of PI3K (1890, 830 and 9000-fold, respectively) and among panel of diverse protein kinases. Western blot has revealed that CPL-302-201 significantly inhibits phosphorylation of Akt in Raji cell line after anti-IgM stimulation (IC50 <50 nM). Additionally, cellular selectivity of the compound against PI3Kg has been confirmed by showing no effect on Akt phosphorylation in RAW 264.7 cell line after C5a stimulation up to 5m M. Currently, CPL-302-201 activity is being further evaluated on series of immune response models.Conclusions:We have designed CPL-302-201 - a novel PI3Kd inhibitor with high potency and outstanding selectivity and preclinical data indicate its therapeutic potential in inflammatory diseases including asthma.
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P. Gunerka, O. Musielak, B. Dymek, D. Zdzalik, M. Zagozda, M. Dziachan, M. Malczyk, A. Bujak, P. Grygielewicz, M. Skupinska, J. Hucz-Kalitowska, K. Dubiel, M. Lamparska-Przybysz, M. Wierczorek, A. Stanczak (Lomianki, Warsaw, Lodz, Poland). Preclinical characterization of CPL-302-201, a novel, highly potent and selective PI3Kδ inhibitor for the treatment of inflammatory disorders. Eur Respir J 2014; 44: Suppl. 58, 1505
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