The hedgehog pathway has been implicated in the tumorigenesis, tumor progression, and metastasis of numerous human cancers. We generated the first fully human hedgehog antibody MEDI-5304 and ...characterized its antitumor activity and preclinical toxicology. MEDI-5304 bound sonic hedgehog (SHH) and Indian hedgehog (IHH) with low picomolar affinity and neutralized SHH and IHH activity in cellular mGLI1 reporter assays. The antibody inhibited transcription of hedgehog target genes and osteoblast differentiation of C3H10T1/2 cells. We evaluated the activity of MEDI-5304 in vivo in model systems that allowed us to evaluate two primary hypotheses of hedgehog function in human cancer, paracrine signaling between tumor and stromal cells and cancer stem cell (CSC) self-renewal. MEDI-5304 displayed robust pharmacodynamic effects in stromal cells that translated to antitumor efficacy as a single agent in an HT-29/MEF coimplantation model of paracrine hedgehog signaling. MEDI-5304 also improved responses to carboplatin in the HT-29/MEF model. The antibody, however, had no effect as a single agent or in combination with gemcitabine on the CSC frequency or growth of several primary pancreatic cancer explant models. These findings support the conclusion that hedgehog contributes to tumor biology via paracrine tumor-stromal signaling but not via CSC maintenance or propagation. Finally, the only safety study finding associated with MEDI-5304 was ondontodysplasia in rats. Thus, MEDI-5304 represents a potent dual hedgehog inhibitor suitable for continued development to evaluate efficacy and safety in human patients with tumors harboring elevated levels of SHH or IHH.
A novel series of nonsteroidal heterocycles was discovered which display cell-type selective, high-affinity (nanomolar) binding to the progesterone receptors from TE85 osteosarcoma cells but > 1 ...microM binding affinity to the progesterone receptors from T47D and ZR75 human breast carcinoma cells. Structure-activity relationships were developed for a set of these compounds, and a representative analog 1-(3,4-dichlorobenzoyl)-3-phenyl-1,4,5,6-tetrahydropyridazine++ + (1i, RWJ 25333) was chosen for further evaluation. RWJ 25333 stimulated the in vitro proliferation of human osteoblast-like cells but not human breast cells.
Mouse ovarian tumor (MOT) cells have been grown in C3HeB/FeJ mice as an ascites and as a subcutaneous tumor and in cell culture as a suspension. These cells contain saturable, high-affinity, specific ...progesterone receptors. Estrogen receptors were not detectable in these cells. MOT cells can be used as both an in vivo and an in vitro model for progestin-mediated radiotherapy.
Fasting is associated with improved outcomes in cancer. Here, we investigated the impact of fasting on natural killer (NK) cell anti-tumor immunity. Cyclic fasting improved immunity against solid and ...metastatic tumors in an NK cell-dependent manner. During fasting, NK cells underwent redistribution from peripheral tissues to the bone marrow (BM). In humans, fasting also reduced circulating NK cell numbers. NK cells in the spleen of fasted mice were metabolically rewired by elevated concentrations of fatty acids and glucocorticoids, augmenting fatty acid metabolism via increased expression of the enzyme CPT1A, and Cpt1a deletion impaired NK cell survival and function in this setting. In parallel, redistribution of NK cells to the BM during fasting required the trafficking mediators S1PR5 and CXCR4. These cells were primed by an increased pool of interleukin (IL)-12-expressing BM myeloid cells, which improved IFN-γ production. Our findings identify a link between dietary restriction and optimized innate immune responses, with the potential to enhance immunotherapy strategies.
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•Cyclic fasting promotes NK cell-mediated anti-tumor immunity•Cyclic fasting promotes metabolic reprogramming of splenic NK cells•Fasting-induced fatty acid oxidation improves the NK cell anti-tumor response•Cyclic fasting redistributes NK cells to the bone marrow, where they are primed by IL-12
Dietary restriction is associated with improved elimination of cancer cells, and fasting regimens are being tested in clinical settings in combination with cancer therapies. Using a cyclic fasting diet (CFD), Delconte et al. show that natural killer (NK) cells undergo tissue redistribution, where the spleen and bone marrow microenvironments metabolically reprogram and prime NK cells to increase anti-tumor function.
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4,5-Disubstituted
cis-pyrrolidinones were investigated as inhibitors of type II 17β-hydroxysteroid dehydrogenase (17β-HSD). Early structure–activity relationship patterns for this ...class of compounds are discussed.
A series of 4,5-disubstituted cis-pyrrolidinones was investigated as inhibitors of 17β-HSD II for the treatment of osteoporosis. Biochemical data for several compounds are given. Compound 42 was ...selected as the lead candidate.
Substituted aminobenzimidazole pyrimidines were synthesized and are shown to display potent biochemical activity against CDK1. Docking studies carried out with a CDK1 homology model provides a ...rationale for the observed activities.
A series of aminobenzimidazole-substituted pyrimidines were synthesized and evaluated for biochemical activity against CDK1. A high-speed parallel synthesis approach enabled the identification of a potent lead series having improved potency in the CDK1 assay (IC
50
<
10
nM). Cell cycle analysis showed that the compounds induced a G2/M block. Docking studies were carried out with a CDK1 homology model, and provide a rationale for the observed activities.
Further investigation of the structural requirements of a series of benzylphosphonic acid inhibitors of human prostatic acid phosphatase has led to the highly potent series of α-aminobenzylphosphonic ...acids. The α-benzylaminobenzylphosphonic acid, with an
IC
50 = 4 nM, exhibited a 3500-fold improvement in potency over the carbon analogue, α-phenylethyl. The enhanced potency may be due to a combination of four favorable interactions including those with the phosphate binding region, the presence the hydrophobic moieties of the benzylamino and phenylphosphonic acid, and a rigid conformer produced by an internal salt bridge between the phosphonate and the α-amino group. Replacement of the phosphonic acid moiety with a phosphinic or carboxylic acid as well as deletion of the benzyl substitution on the α-amino group led to great reductions in potency.
Compound
2A has an IC
50 of 4 nM against the target enzyme. The synthesis, molecular modeling, and SAR of these commpounds are detailed.
A series of 4,5-disubstituted cis-pyrrolidinones was investigated as inhibitors of 17beta-HSD II for the treatment of osteoporosis. Biochemical data for several compounds are given. Compound 42 was ...selected as the lead candidate.
A series of α-substituted benzylphosphonic acids is described as inhibitors of human prostatic acid phosphatase, an enzyme which has been used as a model to study aryl phosphatases. The most potent ...inhibitors in this series are 2-trifluoromethylbenzhydrylphosphonic acid (9 μM), and α-(2-phenylethyl)benzylphosphonic acid (14 μM). The structure-activity studies suggest that bulk tolerance beyond the phosphate binding area limits the steric or hydrophobic contribution to inhibitor potency achieved through α-carbon substitution.
A series of α-substituted benzylphosphonic acids is describes as inhibitors of human prostatic acid phosphatase, an enzyme which has been used as a model to study aryl phosphatases. The most potent inhibitors in this series are 2-trifluoromethylbenzhydrylphosphonic acid (9 μM), and α-(2-phenylethyl) benzylphosphponic acid (14 μM).
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