Human dihydroorotate dehydrogenase (DHODH) is a flavin-dependent mitochondrial enzyme catalyzing the fourth step in the de novo pyrimidine synthesis pathway. It is originally a target for the treatment of the non-neoplastic diseases involving in rheumatoid arthritis and multiple sclerosis, and is re-emerging as a validated therapeutic target for cancer therapy. In this review, we mainly unravel the biological function of DHODH in tumor progression, including its crucial role in de novo pyrimidine synthesis and mitochondrial respiratory chain in cancer cells. Moreover, various DHODH inhibitors developing in the past decades are also been displayed, and the specific mechanism between DHODH and its additional effects are illustrated. Collectively, we detailly discuss the association between DHODH and tumors in recent years here, and believe it will provide significant evidences and potential strategies for utilizing DHODH as a potential target in preclinical and clinical cancer therapies.
The siglecs (sialic acid‐binding Ig‐like lectins) are a distinct subset of the Ig superfamily with adhesion‐molecule‐like structure. We describe here a novel member of the siglec protein family that shares a similar structure including five Ig‐like domains, a transmembrane domain, and a cytoplasmic tail containing two ITIM‐signaling motifs. Siglec‐10 was identified through database mining of an asthmatic eosinophil EST library. Using the Stanford G3 radiation hybrid panel we were able to localize the genomic sequence of siglec‐10 within the cluster of genes on chromosome 19q13.3‐4 that encode other siglec family members. We have demonstrated that siglec‐10 is an immune system‐restricted membrane‐bound protein that is highly expressed in peripheral blood leukocytes as demonstrated by Northern, RT‐PCR and flow cytometry. Binding assays determined that the extracellular domain of siglec‐10 was capable of binding to peripheral blood leukocytes. The cytoplasmic tail of siglec‐10 contains four tyrosines, two of which are embedded in ITIM‐signaling motifs (Y597 and Y667) and are likely involved in intracellular signaling. The ability of tyrosine kinases to phosphorylate the cytoplasmic tyrosines was evaluated by kinase assay using wild‐type siglec‐10 cytoplasmic domain and Y→F mutants. The majority of the phosphorylation could be attributed to Y597 andY667. Further experiments with cell extracts suggest that SHP‐1 interacts with Y667 and SHP‐2 interacts with Y667 in addition to another tyrosine. This is very similar to CD33, which also binds the phosphatases SHP‐1 and SHP‐2, therefore siglec‐10, as CD33, may be characterized as an inhibitory receptor.
Human dihydroorotate dehydrogenase (hDHODH) is an attractive target for cancer therapy. Based on its crystal structure, we designed and synthesized a focused compound library containing the structural moiety of 1,4-benzoquinone, which possesses reactive oxygen species (ROS) induction capacity. Compound 3s with a naphtho[2,3-d][1,2,3]triazole-4,9-dione scaffold exhibited inhibitory activity against hDHODH. Further optimization led to compounds 11k and 11l, which inhibited hDHODH activity with IC50 values of 9 and 4.5 nM, respectively. Protein–ligand cocrystal structures clearly depicted hydrogen bond and hydrophobic interactions of 11k and 11l with hDHODH. Compounds 11k and 11l significantly inhibited leukemia cell and solid tumor cell proliferation and induced ROS production, mitochondrial dysfunction, apoptosis, and cell cycle arrest. Nanocrystallization of compound 11l displayed significant in vivo antitumor effects in the Raji xenograft model. Overall, this study provides a novel bifunctional compound 11l with hDHODH inhibition and ROS induction efficacy, which represents a promising anticancer lead worthy of further exploration.
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...
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.
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