RESUMO
The PI3K/AKT/mTOR and PIM kinase pathways contribute to the development of several hallmarks of cancer. Cotargeting of these pathways has exhibited promising synergistic therapeutic effects in liquid and solid tumor types. To identify molecules with combined activities, we cross-screened our collection of PI3K/(±mTOR) macrocycles (MCXs) and identified the MCX thieno[3,2-d]pyrimidine derivative 2 as a moderate dual PI3K/PIM-1 inhibitor. We report the medicinal chemistry exploration and biological characterization of a series of thieno[3,2-d]pyrimidine MCXs, which led to the discovery of IBL-302 (31), a potent, selective, and orally bioavailable triple PI3K/mTOR/PIM inhibitor. IBL-302, currently in late preclinical development (AUM302), has recently demonstrated efficacy in neuroblastoma and breast cancer xenografts. Additionally, during the course of our experiments, we observed that macrocyclization was essential to obtain the desired multitarget profile. As a matter of example, the open precursors 35-37 were inactive against PIM whereas MCX 28 displayed low nanomolar activity.
RESUMO
Tumors of the nervous system, including neuroblastoma and glioblastoma, are difficult to treat with current therapies. Despite the advances in cancer therapeutics, the outcomes in these patients remain poor and, therefore, new modalities are required. Recent literature demonstrates that cytotoxic effector cells can effectively kill tumors of the nervous system. In addition, we have previously shown that umbilical cord blood (UCB) contains precursors of antitumor cytotoxic effector cells. Therefore, to evaluate the antitumor potential of UCB-derived effector cells, studies were designed to compare the in vitro and in vivo antitumor effects of UCB- and peripheral blood (PB)-derived antigen-nonspecific and antigen-specific effector cells against tumors of the nervous system. Mononuclear cells (MNCs) from UCB were used to generate both interleukin-2 (IL-2)-activated killer (LAK) cells and tumor-specific cytotoxic T lymphocytes (CTLs). UCB-derived LAK cells showed a significant in vitro cytotoxicity against IMR-32, SK-NMC, and U-87 human neuroblastoma and glioblastoma, respectively. In addition, the CTLs generated using dendritic cells primed with IMR-32 tumor cell lysate showed a selective cytotoxicity in vitro against IMR-32 cells, but not against U-87 or MDA-231 cells. Furthermore, treatment of SCID mice bearing IMR-32 neuroblastoma with tumor-specific CTLs resulted in a significant (p < 0.01) inhibition of tumor growth and increased overall survival. Thus, these results demonstrate the potential of UCB-derived effector cells against human neuroblastoma and warrant further preclinical studies.
