Mark Laurence Boys

5-Alkyl-2-urea-Substituted Pyridines: Identification of Efficacious Glucokinase Activators with Improved Properties

Two 1-(4-aryl-5-alkyl-pyridin-2-yl)-3-methylurea glucokinase activators were identified with robust in vivo efficacy. These two compounds possessed higher solubilities than the previously identified triaryl compounds (i.e., AM-2394). Structure–activity relationship studies are presented along with relevant pharmacokinetic and in vivo data.

Abstract 551: A potent and selective cFMS inhibitor regulates the tumor macrophage microenvironment leading to tumor growth inhibition

Increasing evidence suggests that interactions between tumor cells, stromal cells, macrophages and the extracellular matrix are pivotal to the processes of tumorigenesis, metastasis, and neovascularization. Macrophages within the tumor microenvironment are thought to facilitate cancer progression, making them intriguing targets for therapy. Colony stimulating factor 1 (CSF-1) and its receptor, cFMS, play a central role in the development of mononuclear phagocytes, recruitment of macrophages to tumors, and differentiation and function of osteoclasts. We have developed an orally active, selective small-molecule cFMS inhibitor for cFMS. This molecule inhibits cFMS cellular activity (IC 50 = 9 nM) in vitro and inhibits cFMS phosphorylation in a transfected cell line grown in nude mice (ED 50 = 3 mg/kg). Our compound also inhibits CSF-1-mediated osteoclast differentiation and function (IC 50 values of = 4 nM and 58 nM, respectively). To further explore the potential of our selective inhibitor for the treatment of cancer, we evaluated anti-tumor activity in several preclinical models. We first explored the effect on the murine ovarian cancer cell line, ID8. ID8 cells injected intraperitoneally into nude mice form multiple peritoneal tumor deposits and abundant ascites. Macrophage infiltration in the ID8 ascites was markedly lowered in mice treated with a cFMS inhibitor. Using MCF-7, a human breast adenocarcinoma cell line that has been shown to produce M-CSF, a daily oral dose with 100 mg/kg of our inhibitor for 21 days significantly reduced tumor growth and was accompanied by a marked reduction in tumor-associated macrophages. These findings support the potential of a selective inhibitor of cFMS to favorably impact human cancers by modulating tumor-associated macrophage functions. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 551. doi:10.1158/1538-7445.AM2011-551

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.