This letter describes the discovery of a novel series of tetrahydroisoquinoline (THIQ)-derived small molecules that potently inhibit both human T-cell migration and super-antigen induced T-cell activation through disruption of the binding of integrin LFA-1 to its receptor, ICAM-1. In addition to excellent in vitro potency, 6q shows good pharmacokinetic properties and its ethyl ester (6t) demonstrates good oral bioavailability in both mouse and rat. Either intravenous administration of 6q or oral administration of its ethyl ester (6t) produced a significant reduction of neutrophil migration in a thioglycollate-induced murine peritonitis model.

This communication describes the discovery of a novel series of Aurora kinase inhibitors. Key SAR and critical binding elements are discussed. Some of the more advanced analogues potently inhibit cellular proliferation and induce phenotypes consistent with Aurora kinase inhibition. In particular, compound 21 (SNS-314) is a potent and selective Aurora kinase inhibitor that exhibits significant activity in pre-clinical in vivo tumor models.

Proc Amer Assoc Cancer Res, Volume 47, 2006 4726 SNS-595 is a novel naphthyridine analog that acts specifically during the S-phase to induce rapid apoptosis of cells that are actively synthesizing DNA, resulting in cell cycle arrest in the G2 phase. SNS-595 is being developed for the treatment of both solid and hematologic malignancies. Current treatment of relapsed or refractory acute leukemias and advanced chronic myelogenous leukemia remains suboptimal. In patients with acute myelogenous leukemia (AML), failure to achieve a complete remission (CR) after induction chemotherapy or relapse occurring within the first year after diagnosis is associated with a poor prognosis. In patients with accelerated or blast-phase chronic myelogenous leukemia (CML) the response rates to intensive chemotherapy regimens are less than 30%, and in responding patients the median remission duration averages 4 to 6 months. SNS-595 has potent anti-proliferative effects on human leukemic cell lines in vitro. IC50 values, determined by MTT assay in four human promyelocytic, and acute lymphoblastic leukemia cell lines, range from 40 to 170 nM. Intravenous administration of SNS-595 to nu/nu mice with LM-3 Jck hematologic xenograft tumors resulted in 97 to 99% tumor growth inhibition. All mice treated with SNS-595 had significant reductions in tumor volume, with a complete response rate of 67%. Similarly, SNS-595 also showed 98% tumor growth inhibition in mice bearing CCRF-CEM xenograft tumors. The effect of IV administered SNS-595 on bone-marrow cellularity and circulating levels of leukocytes in CD-1 mice was measured after drug administration on days 0 and 4. Two days after the second administration of SNS-595, bone marrow isolated from femurs showed a dose-dependent reduction in cellularity. At 20 mg/kg, cellularity was reduced to 7.5%, while circulating neutrophils were reduced from a pre-dose level of 1244 ±55 cells/μL to a nadir of 51 ±24 cells/μL blood on day 8. Absolute neutrophil counts subsequently rebounded and soon returned to normal levels. Total WBCs also reached a nadir on day 8, but returned to normal levels. In conclusion, in vitro and in vivo data show that SNS-595 has potent anti-proliferative activity on human leukemic cell lines, inhibits tumor growth in hematologic xenografts, and reversibly ablates murine bone marrow cells. These data suggest that SNS-595 has the potential to demonstrate important clinical activity in patients with hematologic malignancies.

Despite advances in the treatment of leukemia patients, response rates with intensive chemotherapy regimens remain less than 30% for relapsed or refractory acute leukemias and advanced chronic myelogenous leukemias. SNS-595, is a novel naphthyridine analog small molecule, a class of drugs not previously used in cancer treatment. SNS-595 acts specifically during the S-phase of the cell cycle to induce rapid apoptosis of cells that are actively synthesizing DNA, and a subsequent cell cycle arrest in the G2 phase of the cell cycle. Sunesis Pharmaceuticals, Inc., is developing SNS-595 for the treatment of both solid and hematologic malignancies. SNS-595 was previously evaluated in two models of hematologic cancer in nu / nu mice, causing a dose-dependent tumor growth inhibition (97% to 99%, n=6 mice per treatment group) in a LM-3 Jck (human acute lymphoma) hematologic xenograft. All 6 mice treated at 30 mg/kg had a major reduction in tumor volume, with 2 mice showing a complete response. SNS-595 also significantly inhibited tumor growth in mice bearing CCRF-CEM (human acute lymphoblastic leukemia) xenograft tumors. In phase I clinical trials in solid tumors the dose-limiting toxicity was neutropenia, and the incidence of gastrointestinal effects, nausea, and vomiting was low. No mucositis or peripheral neuropathies were observed. In the present study, CD1 mice (n=4 per treatment group) were administered either SNS-595 15 mg/kg or 20 mg/kg, by IV bolus on days 0 and 4, or the S-phase acting drug, cytarabine (Ara-C) 150 mg/kg, BID, by IP injection on days 0 and 4. SNS-595 was well tolerated, with no body weight loss observed through to day 16. Bone marrow isolated from the femurs showed a dose-dependent reduction in cellularity on day 6, 48hr after the second of the two SNS-595 administrations; at 15 and 20 mg/kg, cellularity was reduced to 15% (±2.9, n=4) and 7.5% (±1.4, n=4) respectively. SNS-595, 20 mg/kg, reduced absolute neutrophils to a nadir of 51 ±24 cells/μL blood (n=4) on day 8, from 1244 ±55 cells/μL at day 0 (n=4), but subsequently rebounded to normal levels by day 16. Total WBCs also reached a nadir on day 8, returning to normal by day 16. In the same timeframe cytarabine caused bone marrow ablation, with absolute neutrophil counts substantially reduced at day 8 and returning to normal by day 16. In conclusion SNS-595 has significant anti-tumor activity in hematologic xenografts, as well as significant ability to reversibly ablate murine bone marrow cells. These properties, combined with the good clinical safety profile observed in phase I patients, suggest that SNS-595 has the potential to demonstrate anti-tumor activity in patients with hematologic malignancies.