N-Acyl-2-aminothiazoles with nonaromatic acyl side chains containing a basic amine were found to be potent, selective inhibitors of CDK2/cycE which exhibit antitumor activity in mice. In particular, compound 21 [N-[5-[[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide, BMS-387032], has been identified as an ATP-competitive and CDK2-selective inhibitor which has been selected to enter Phase 1 human clinical trials as an antitumor agent. In a cell-free enzyme assay, 21 showed a CDK2/cycE IC(50) = 48 nM and was 10- and 20-fold selective over CDK1/cycB and CDK4/cycD, respectively. It was also highly selective over a panel of 12 unrelated kinases. Antiproliferative activity was established in an A2780 cellular cytotoxicity assay in which 21 showed an IC(50) = 95 nM. Metabolism and pharmacokinetic studies showed that 21 exhibited a plasma half-life of 5-7 h in three species and moderately low protein binding in both mouse (69%) and human (63%) serum. Dosed orally to mouse, rat, and dog, 21 showed 100%, 31%, and 28% bioavailability, respectively. As an antitumor agent in mice, 21 administered at its maximum-tolerated dose exhibited a clearly superior efficacy profile when compared to flavopiridol in both an ip/ip P388 murine tumor model and in a s.c./i.p. A2780 human ovarian carcinoma xenograft model.

Clinical validation of S1P receptor modulation therapy was achieved with the approval of fingolimod (Gilenya, 1) as the first oral therapy for relapsing remitting multiple sclerosis. However, 1 causes a dose-dependent reduction in the heart rate (bradycardia), which occurs within hours after first dose. We disclose the identification of clinical compound BMS-986104 (3d), a novel S1P 1 receptor modulator, which demonstrates ligand-biased signaling and differentiates from 1 in terms of cardiovascular and pulmonary safety based on preclinical pharmacology while showing equivalent efficacy in a T-cell transfer colitis model. KEYWORDS: GPCR, S1P1, S1P3, biased signaling L ymphocyte infiltration from blood into sites of inflammation is critical to the pathogenesis of autoimmune diseases and allograft rejection. Gilenya (FTY720, 1) blocks lymphocyte migration through sequestration of lymphocytes in the thymus and secondary lymphoid organs, leading to a marked lymphopenia. 1 Compound 1 is a pro-drug; its phosphorylated form, FTY-P (1-P), binds four out of the five S1P receptors (S1P-1, 3, 4, 5) and elicits a full agonist response in functional assays such as GTP-S binding, ERK phosphorylation, cAMP, and calcium mobilization. Among these four receptors, S1P 1 has been shown to be critically involved in lymphocyte trafficking and agonism of this receptor is responsible for the peripheral blood lymphopenia believed to be key to the efficacy seen with 1. 2,3 Clinical studies have demonstrated a side effect profile of 1 that includes cardiovascular effects (transient bradycardia, sustained blood pressure elevation) as well as a decline in pulmonary function. 4 In rodent studies, S1P 3 activity was shown to play a role in some of the observed acute toxicity of nonselective S1P receptor agonists, including bradycardia, hypertension, and bronchoconstriction. 5,6 As agonism of S1P 3 does not appear to contribute to efficacy, the identification of S1P 1 agonists sparing of S1P 3 has been a primary emphasis of many research programs in this area. 7 However, clinical studies with S1P agonists with selectivity for S1P 1 over S1P 3 have suggested that in humans the heart rate reduction effects are controlled at least in part through agonism of S1P 1 . 8 Additionally, through the course of our own studies it was discovered that simply abolishing S1P 3 agonism was not sufficient to eliminate the acute and chronic pulmonary toxicity elicited in rodents by 1 or by selective S1P 1 full agonists, findings that led us to discontinue our efforts related to S1P 1 full agonists and seek alternative profiles that could overcome these liabilities. 9 In this letter we describe the identification of a differentiated S1P 1 receptor modulator, BMS-986104 (3d), which distinguishes itself from 1 in terms of cardiovascular and pulmonary safety based on preclinical pharmacology while showing equivalent efficacy in a T-cell transfer colitis model.In our search for S1P 1 agonists that could further dissociate efficacy from toxicity, we evaluated...

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Recently, our research group reported the identification of BMS-986104 (2) as a differentiated S1P 1 receptor modulator. In comparison to fingolimod (1), a full agonist of S1P 1 currently marketed for the treatment of relapse remitting multiple sclerosis (RRMS), 2 offers several potential advantages having demonstrated improved safety multiples in preclinical evaluations against undesired pulmonary and cardiovascular effects. In clinical trials, 2 was found to exhibit a pharmacokinetic half-life (T 1/2 ) longer than that of 1, as well as a reduced formation of the phosphate metabolite that is required for activity against S1P 1 . Herein, we describe our efforts to discover highly potent, partial agonists of S1P 1 with a shorter T 1/2 and increased in vivo phosphate metabolite formation. These efforts culminated in the discovery of BMS-986166 (14a), which was advanced to human clinical evaluation. The pharmacokinetic/pharmacodynamic (PK/PD) relationship as well as pulmonary and cardiovascular safety assessments are discussed. Furthermore, efficacy of 14a in multiple preclinical models of autoimmune diseases are presented.

FTY720 (also called fingolimod) is recognized as an immunosuppressant and has been approved by the Food and Drug Administration to treat refractory multiple sclerosis. However, long-term administration of FTY720 potentially increases the risk for cancer in recipients. The underlying mechanisms remain poorly understood. Herein, we provided evidence that FTY720 administration potentiated tumor growth. Mechanistically, FTY720 enhanced extramedullary hematopoiesis and massive accumulation of myeloid-derived suppressor cells (MDSCs), which actively suppressed antitumor immune responses. Granulocyte-macrophage colony-stimulating factor (GM-CSF), mainly produced by MDSCs, was identified as a key factor to mediate these effects of FTY720 in tumor microenvironment. Furthermore, we showed that FTY720 triggers MDSCs to release GM-CSF via S1P receptor 3 (S1pr3) through Rho kinase and extracellular signal-regulated kinase-dependent pathway. Thus, our findings provide mechanistic explanation for the protumorigenic potentials of FTY720 and suggest that targeting S1pr3 simultaneously may be beneficial for the patients receiving FTY720 treatment.

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Scaffold hopping and structure-based drug design were employed to identify substituted 4-aminoquinolines and 4-aminonaphthyridines as potent, small molecule inhibitors of tumor necrosis factor alpha (TNFα). Structure–activity relationships in both the quinoline and naphthyridine series leading to the identification of compound 42 with excellent potency and pharmacokinetic profile are discussed. X-ray co-crystal structure analysis and ultracentrifugation experiments clearly demonstrate that these inhibitors distort the TNFα trimer upon binding, leading to aberrant signaling when the trimer binds to TNF receptor 1 (TNFR1). Pharmacokinetic–pharmacodynamic activity of compound 42 in a TNF-induced IL-6 mouse model and in vivo activity in a collagen antibody-induced arthritis model, where it showed biologic-like in vivo efficacy, will be discussed.