La presente invention concerne des composes de formule (I) ou (II) et leurs sels, ainsi que des m... more La presente invention concerne des composes de formule (I) ou (II) et leurs sels, ainsi que des methodes d'utilisation desdits composes pour le traitement du cancer.
Results: Dose response testing showed 2/4 neuroblastoma and 3/3 ALL models achieving an objective... more Results: Dose response testing showed 2/4 neuroblastoma and 3/3 ALL models achieving an objective response at 10 mg/kg (50% of MTD), with the most sensitive neuroblastoma model (NB-1643) achieving an objective response at 5 mg/kg and with 2/3 ALL models showing good leukemia growth control during treatment at 5 mg/kg. Two additional neuroblastomas were not responsive to MLN8237 at a dose of 20 mg/kg. MLN8237 induced an increase in mitotic index and %pHistH3 positive cells following a single dose of agent that peaked at 12 hrs, returning to baseline levels within 24 hrs. Conclusions: Dose response testing indicates MLN8237 efficacy at 50% of its MTD in a subset of responsive neuroblastoma and ALL models. PD studies are consistent with in vivo anti-neuroblastoma activity through inhibition of Aurora A kinase. Further preclinical studies of MLN8237 focusing on combinations with other agents are anticipated, and pediatric clinical development of MLN8237 is proceeding. (Supported by NCI NO1CM42216.
A series of potent dual JAK1/3 inhibitors have been developed from a moderately selective JAK3 in... more A series of potent dual JAK1/3 inhibitors have been developed from a moderately selective JAK3 inhibitor. Substitution at the C6 position of the pyrrolopyridazine core with aryl groups provided exceptional biochemical potency against JAK1 and JAK3 while maintaining good selectivity against JAK2 and Tyk2. Translation to in vivo efficacy was observed in a murine model of chronic inflammation. X-ray co-crystal structure determination confirmed the presumed inhibitor binding orientation in JAK3. Efforts to reduce hERG channel inhibition will be described.
Bioorganic & medicinal chemistry letters, Jan 15, 2015
The discovery, synthesis, and characterization of 9H-carbazole-1-carboxamides as potent and selec... more The discovery, synthesis, and characterization of 9H-carbazole-1-carboxamides as potent and selective ATP-competitive inhibitors of Janus kinase 2 (JAK2) are discussed. Optimization for JAK family selectivity led to compounds 14 and 21, with greater than 45-fold selectivity for JAK2 over all other members of the JAK kinase family.
La presente invention concerne des composes de formule (I) ou (II) et leurs sels, ainsi que des m... more La presente invention concerne des composes de formule (I) ou (II) et leurs sels, ainsi que des methodes d'utilisation desdits composes pour le traitement du cancer.
Results: Dose response testing showed 2/4 neuroblastoma and 3/3 ALL models achieving an objective... more Results: Dose response testing showed 2/4 neuroblastoma and 3/3 ALL models achieving an objective response at 10 mg/kg (50% of MTD), with the most sensitive neuroblastoma model (NB-1643) achieving an objective response at 5 mg/kg and with 2/3 ALL models showing good leukemia growth control during treatment at 5 mg/kg. Two additional neuroblastomas were not responsive to MLN8237 at a dose of 20 mg/kg. MLN8237 induced an increase in mitotic index and %pHistH3 positive cells following a single dose of agent that peaked at 12 hrs, returning to baseline levels within 24 hrs. Conclusions: Dose response testing indicates MLN8237 efficacy at 50% of its MTD in a subset of responsive neuroblastoma and ALL models. PD studies are consistent with in vivo anti-neuroblastoma activity through inhibition of Aurora A kinase. Further preclinical studies of MLN8237 focusing on combinations with other agents are anticipated, and pediatric clinical development of MLN8237 is proceeding. (Supported by NCI NO1CM42216.
A series of potent dual JAK1/3 inhibitors have been developed from a moderately selective JAK3 in... more A series of potent dual JAK1/3 inhibitors have been developed from a moderately selective JAK3 inhibitor. Substitution at the C6 position of the pyrrolopyridazine core with aryl groups provided exceptional biochemical potency against JAK1 and JAK3 while maintaining good selectivity against JAK2 and Tyk2. Translation to in vivo efficacy was observed in a murine model of chronic inflammation. X-ray co-crystal structure determination confirmed the presumed inhibitor binding orientation in JAK3. Efforts to reduce hERG channel inhibition will be described.
Bioorganic & medicinal chemistry letters, Jan 15, 2015
The discovery, synthesis, and characterization of 9H-carbazole-1-carboxamides as potent and selec... more The discovery, synthesis, and characterization of 9H-carbazole-1-carboxamides as potent and selective ATP-competitive inhibitors of Janus kinase 2 (JAK2) are discussed. Optimization for JAK family selectivity led to compounds 14 and 21, with greater than 45-fold selectivity for JAK2 over all other members of the JAK kinase family.
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