Jon H. Come

2-Aminopyrazolo[1,5-a]pyrimidines as potent and selective inhibitors of JAK2.

Constitutive activation of the EPO/JAK2 signaling cascade has recently been implicated in a variety of myeloproliferative disorders including polycythemia vera, essential thrombocythemia and myelofibrosis. In an effort to uncover therapeutic potential of blocking the EPO/JAK2 signaling cascade, we sought to discover selective inhibitors that block the kinase activity of JAK2. Herein, we describe the discovery and structure based optimization of a novel series of 2-amino-pyrazolo[1,5-a]pyrimidines that exhibit potent inhibition of JAK2.

4-(Benzimidazol-2-yl)-1,2,5-oxadiazol-3-ylamine derivatives: potent and selective p70S6 kinase inhibitors.

We report herein the design and synthesis of 4-(benzimidazol-2-yl)-1,2,5-oxadiazol-3-amine derivatives as inhibitors of p70S6 kinase. Screening hits containing the 4-(benzimidazol-2-yl)-1,2,5-oxadiazol-3-ylamine scaffold were optimized for p70S6K potency and selectivity against related kinases. Structure-based design employing an active site homology model derived from PKA led to the preparation of benzimidazole 5-substituted compounds 26 and 27 as highly potent inhibitors (K(i) <1nM) of p70S6K, with >100-fold selectivity against PKA, ROCK and GSK3.

Design and Synthesis of a Novel Series of Orally Bioavailable, CNS-Penetrant, Isoform Selective Phosphoinositide 3-Kinase γ (PI3Kγ) Inhibitors with Potential for the Treatment of Multiple Sclerosis (MS)

The lipid kinase phosphoinositide 3-kinase γ (PI3Kγ) has attracted attention as a potential target to treat a variety of autoimmune disorders, including multiple sclerosis, due to its role in immune modulation and microglial activation. By minimizing the number of hydrogen bond donors while targeting a previously uncovered selectivity pocket adjacent to the ATP binding site of PI3Kγ, we discovered a series of azaisoindolinones as selective, brain penetrant inhibitors of PI3Kγ. This ultimately led to the discovery of 16, an orally bioavailable compound that showed efficacy in murine experimental autoimmune encephalomyelitis (EAE), a preclinical model of multiple sclerosis.

ROCK inhibitors 3: Design, synthesis and structure-activity relationships of 7-azaindole-based Rho kinase (ROCK) inhibitors.

Rho kinase (ROCK) inhibitors are potential therapeutic agents for the treatment of a variety of disorders including hypertension, glaucoma and erectile dysfunction. Here we disclose a series of potent and selective ROCK inhibitors based on a substituted 7-azaindole scaffold. Substitution of the 3-position of 7-azaindole led to compounds such as 37, which possess excellent ROCK inhibitory potency and high selectivity against the closely related kinase PKA.

Abstract LB-B15: A novel PI3K gamma isoform selective small molecule kinase inhibitor demonstrates single agent anti-tumor activity and enhanced combination activity with checkpoint blockade in syngeneic mouse models of cancer

Immune checkpoint inhibitors have generated impressive clinical responses, however, a number of patients and cancer types remain resistant to checkpoint blockade. Immunosuppressive cells such as Tregs and MDSCs in the tumor microenvironment are hypothesized to mediate this resistance. The gamma (γ) isoform of PI3K has long been known to modulate myeloid and lymphocyte cell migration and function, including trafficking of monocytic and granulocytic cells into inflamed tissues such as tumors. Here we report the identification and characterization of BVD-723, a PI3Kγ selective small molecule kinase inhibitor which demonstrated single agent and enhanced combination anti-tumor activity[xx]with either an anti-PD-1 or anti-CTLA-4 antibody. In a mouse syngeneic colon cancer model,[xx]BVD-723 in combination with anti-PD-1 or anti-CTLA-4 resulted in complete regression[xx]of tumors in 35% (7/20) and 60% (12/20) of animals treated with each antibody respectively [versus 0% (0/20) and 5% (1/20) with either antibody alone]. Interestingly, the anti-tumor activity was coupled with a decrease in tumor infiltrating Tregs, granulocytic MDSCs, CD4+ T cells and an increase in the CD8+/Treg ratio, suggesting that inhibition of PI3Kγ by BVD-723 promotes immune-reactivation in the tumor microenvironment. Additionally, BVD-723 demonstrated potent synergy with an anti-PD-1 antibody in a syngeneic mouse model of lymphoma. Single agent BVD-723 activity was also observed in syngeneic mouse models of pancreas, colon, lymphoma and bladder cancers. Results from completed safety pharmacology, toxicology and in vivo efficacy studies support clinical evaluation of BVD-723[xx]as a monotherapy or in combination with the checkpoint inhibitors in cancer.[xx] Citation Format: Saurabh Saha, Linping Zhang, Thomas Hoock, Alex Aronov, Sudipta Mahajan, Michael Boyd, Jon Come, Veronique Damagnez, Wojciech Dworakowski, Suvarna Khare-Pandit, Arnaud LeTiran, Cameron Moody, Harwin O9Dowd, Joseph Prezioso, Setu Roday, Xiaoyan M. Zhang. A novel PI3K gamma isoform selective small molecule kinase inhibitor demonstrates single agent anti-tumor activity and enhanced combination activity with checkpoint blockade in syngeneic mouse models of cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr LB-B15.