John P. Fischer

3-Hydroxyisoquinolines as inhibitors of HCV NS5b RNA-dependent RNA polymerase.

Isoquinoline-based non-nucleoside inhibitors of HCV NS5b RNA-dependent RNA-polymerase are described. The synthesis and structure-activity relationships are detailed, along with enzyme and cellular activity.

Non-nucleoside inhibitors of HCV NS5B polymerase. Part 1: Synthetic and computational exploration of the binding modes of benzothiadiazine and 1,4-benzothiazine HCV NS5b polymerase inhibitors.

The importance of internal hydrogen bonding in a series of benzothiadiazine and 1,4-benzothiazine NS5b inhibitors has been explored. Computational analysis has been used to compare the protonated vs. anionic forms of each series and we demonstrate that activity against HCV NS5b polymerase is best explained using the anionic forms. The syntheses and structure-activity relationships for a variety of new analogs are also discussed.

Abstract 4484: AR-mTOR-26 - A potent, selective mTORC 1/2 kinase inhibitor for the treatment of malignancy

As a consequence of a variety of genetic lesions, the PI3K/Akt pathway is constitutively activated in a large proportion of human cancers. The mTOR kinase plays an important role in this pathway as the key component of two independent signaling complexes (TORC1 and TORC2) that are involved at two distinct levels in this signaling cascade. Accordingly, inhibition of mTOR kinase will abrogate signaling from both mTOR complexes and serve as an effective means of targeting this pathway. In addition, the activity of the TORC1 complex is often aberrantly activated in a PI3K-independent manner to allow tumor cells to survive and proliferate despite the many negative influences of the tumor microenvironment such as hypoxia and limited nutrient availability. Therefore, an inhibitor of both TORC1 and TORC2 should effectively block signaling from the PI3K pathway as well as abrogate the cancer cells’ ability to survive in the harsh environment of the tumor thereby providing an effective means of treating cancer. We report here the profile of our small molecule mTOR kinase inhibitor AR-mTOR-26. On enzyme, this compound inhibits mTOR kinase with an IC 50 of 1 nM while exhibiting substantial selectivity against PI3Kα as well as a panel of lipid and protein kinases. In cells, AR-mTOR-26 inhibits the TORC1-dependent readouts pS6 (Ser235/6) and p4E-BP1 (Ser37/46) as well as the TORC2 phosphorylation site on Akt, Ser473, with IC 50 values of G12D /PIK3CA]. These effects ranged from tumor growth inhibition to regressions dependent upon the dose and the xenograft model evaluated. In all, these data show that targeting mTOR kinase with AR-mTOR-26 holds promise as a broadly acting therapeutic for oncology. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4484.

Abstract B267: AR‐mTOR‐1: A potent, selective mTORC 1/2 kinase inhibitor for the treatment of malignancy

Through alterations in the PTEN and PI3K genes, the PI3K / Akt pathway is constitutively activated in human cancers. mTOR kinase plays an unique role in this pathway as the key component of two independent signaling complexes (mTORC1 (raptor ‐ rapamycin sensitive) and mTORC2 (rictor ‐ rapamycin insensitive)) that are involved at multiple branch points in this signaling cascade. As such, inhibition of mTOR kinase inactivates both mTOR complexes and therefore serves as an attractive means to target this integral pathway for the treatment of human malignancy. We report the biological and pharmaceutical evaluation of our selective mTOR 1/2 kinase inhibitor AR‐mTOR‐1. AR‐mTOR‐1 inhibits mTOR kinase with an IC50 of Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B267.