Tag: M.W=600-700

Mahalingam, Devalingam published the artcilePhase 1 open-label, multicenter study of first-in-class ROR¦Ã Agonist LYC-55716 (cintirorgon): safety, tolerability, and preliminary evidence of antitumor activity, Application In Synthesis of 2055536-64-4, the publication is Clinical Cancer Research (2019), 25(12), 3508-3516, database is CAplus and MEDLINE.

Transcription factor retinoic acid receptor-related orphan receptor ¦Ã (ROR¦Ã) regulates type 17 effector T-cell differentiation and function and is key to immune cell regulation. A phase 1 study evaluated the safety and tolerability of LYC-55716 (cintirorgon), a first-in-class, oral, small-mol. ROR¦Ã agonist in adults with relapsed/refractory metastatic cancer. Patients received 28-day treatment cycles of oral LYC-55716; dose and dosing regimen were determined according to pharmacokinetic profile and safety. No dose-limiting toxicities occurred among the 32 enrolled patients who received LYC-55716 150 mg BID to 450 mg BID. Treatment-related adverse events (AE) were primarily grade 1-2 and included diarrhea (n = 11), fatigue (n = 7), anemia (n = 4), decreased appetite (n = 4), and nausea (n = 4). Grade 3 AEs were anemia (n = 2), elevated gamma-glutamyl transferase (n = 1), and hypophosphatemia (n = 1). Two patients (NSCLC and sarcomatoid breast cancer) had confirmed partial responses; 11 had disease stabilization for 2 to 12 mo (6 received >4 mo of treatment). Ese data support the safety and tolerability of LYC-55716 and selection of 450 mg BID dose for a phase 2a study assessing LYC-55716 clin. activity, safety, and biomarkers in patients with NSCLC, head and neck, gastroesophageal, renal cell, urothelial, and ovarian cancers.

Clinical Cancer Research published new progress about 2055536-64-4. 2055536-64-4 belongs to catalysis-chemistry, auxiliary class Metabolic Enzyme,ROR, name is (S)-3-(6-(3-(Difluoromethoxy)-5-fluorophenyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)-2,2-dimethylpropanoic acid, and the molecular formula is C27H23F6NO6S, Application In Synthesis of 2055536-64-4.

Referemce:
https://courses.lumenlearning.com/boundless-chemistry/chapter/catalysis/,
Catalysis – Wikipedia

Aicher, Thomas D. published the artcileDiscovery of LYC-55716: A Potent, Selective, and Orally Bioavailable Retinoic Acid Receptor-Related Orphan Receptor-¦Ã (ROR¦Ã) Agonist for Use in Treating Cancer, Recommanded Product: (S)-3-(6-(3-(Difluoromethoxy)-5-fluorophenyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)-2,2-dimethylpropanoic acid, the publication is Journal of Medicinal Chemistry (2021), 64(18), 13410-13428, database is CAplus and MEDLINE.

Retinoic acid receptor-related orphan receptor ¦Ã (RORc, ROR¦Ã, or NR1F3) is the nuclear receptor master transcription factor that drives the function and development of IL-17-producing T helper cells (Th17), cytotoxic T cells (Tc17), and subsets of innate lymphoid cells. Activation of ROR¦Ã⁺ T cells in the tumor microenvironment is hypothesized to render immune infiltrates more effective at countering tumor growth. To test this hypothesis, a family of benzoxazines was optimized to provide LYC-55716 (37c), a potent, selective, and orally bioavailable small-mol. ROR¦Ã agonist. LYC-55716 decreases tumor growth and enhances survival in preclin. tumor models and was nominated as a clin. development candidate for evaluation in patients with solid tumors.

Journal of Medicinal Chemistry published new progress about 2055536-64-4. 2055536-64-4 belongs to catalysis-chemistry, auxiliary class Metabolic Enzyme,ROR, name is (S)-3-(6-(3-(Difluoromethoxy)-5-fluorophenyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)-2,2-dimethylpropanoic acid, and the molecular formula is C27H23F6NO6S, Recommanded Product: (S)-3-(6-(3-(Difluoromethoxy)-5-fluorophenyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)-2,2-dimethylpropanoic acid.

Referemce:
https://courses.lumenlearning.com/boundless-chemistry/chapter/catalysis/,
Catalysis – Wikipedia

Xia, Li published the artcileROR¦Ãt agonist enhances anti-PD-1 therapy by promoting monocyte-derived dendritic cells through CXCL10 in cancers, Category: catalysis-chemistry, the publication is Journal of Experimental & Clinical Cancer Research (2022), 41(1), 155, database is CAplus and MEDLINE.

The overall response rate to checkpoint blockade remains unsatisfactory, partially due to the immune-suppressive tumor microenvironment. A retinoic acid-related orphan receptor ¦Ãt (ROR¦Ãt) agonist (LYC-55716) is currently used in clin. trials combined with anti-PD-1, but how the Th17 cell transcription factor ROR¦Ãt enhances antitumor immunity of PD-1 in the tumor microenvironment remains elusive. The expression of mRNA was analyzed using qPCR assays. Flow cytometry was used to sort and profile cells. Cell migration was analyzed using Transwell assays. Biacore was used to determine the binding affinity to the ROR¦Ãt protein. The ROR¦Ãt GAL4 cell-based reporter gene assay was used to measure activity in the ROR¦Ãt driven luciferase reporter gene expression. We designed a potent and selective small-mol. ROR¦Ãt agonist (8-074) that shows robust antitumor efficacy in syngeneic tumor models and improves the efficacy of anti-PD-1 in a murine lung cancer model. ROR¦Ãt agonist treatment increased intratumoral CD8+ T cells, which were correlated with CXCL10 and monocyte-derived dendritic cells (MoDCs). In addition, the ROR¦Ãt agonist promoted Type 17 T cell migration by upregulating CCL20 and CCR6 expression, and Type 17 T cell tumor infiltration. CCL20 induces MoDCs migration, and CXCL10 derived from MoDCs promotes CD8+ T cell migration. Our results revealed that the ROR¦Ãt agonist improved the efficacy of anti-PD-1. The ROR¦Ãt agonist increased the migration of MoDCs, which increased the local levels of CXCL10, thus promoting CD8+ T cell tumor infiltration. Our findings provide the mechanistic insights implicating the ROR¦Ãt agonist in immunotherapy and offer a strategy for targeting the ROR¦Ãt agonist to improve PD-1 antibody efficacy in cancers.

Journal of Experimental & Clinical Cancer Research published new progress about 2055536-64-4. 2055536-64-4 belongs to catalysis-chemistry, auxiliary class Metabolic Enzyme,ROR, name is (S)-3-(6-(3-(Difluoromethoxy)-5-fluorophenyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)-2,2-dimethylpropanoic acid, and the molecular formula is C20H18BrN3, Category: catalysis-chemistry.

Referemce:
https://courses.lumenlearning.com/boundless-chemistry/chapter/catalysis/,
Catalysis – Wikipedia

Zhu, Yan published the artcileDiscovery of aryl-substituted indole and indoline derivatives as ROR¦Ãt agonists, Formula: C27H23F6NO6S, the publication is European Journal of Medicinal Chemistry (2019), 111589, database is CAplus and MEDLINE.

A series of aryl-substituted indole and indoline derivatives were discovered as novel ROR¦Ãt agonists by a scaffold-based hybridization of the reported ROR¦Ãt agonists 1 and 2. SAR studies on the core structures, the RHS hydrophilic side chains and the LHS hydrophobic aryl groups of a hybrid compound 3 led to the identification of potent ROR¦Ãt agonists with improved drug-like properties. Compound 14 represented a high potency lead with an EC₅₀ of 20.8 ¡À 1.5 nM, the (S)-enantiomer (EC₅₀ = 16.1 ¡À 4.5 nM) of which was 17 times more potent than the (R) counterpart (EC₅₀ = 286 ¡À 30.4 nM) in ROR¦Ã dual FRET assay. The cell-based GAL4 reporter gene assay also suggested 14 as the most active compound which exhibited an EC₅₀ of 247 ¡À 33.1 nM and a maximum activation percentage of 133%. Moreover, 14 showed high metabolic stability (t_1/2 = 113 min) in mouse liver microsome and had improved aqueous solubility at pH 7.4 compared to the parent compounds Furthermore, 14 was found to be orally bioavailable and demonstrated excellent in vivo pharmacokinetics in mice. Present studies indicate that 14 deserves further investigation in tumor animal models as a potential candidate of ROR¦Ãt agonist for cancer immunotherapy.

European Journal of Medicinal Chemistry published new progress about 2055536-64-4. 2055536-64-4 belongs to catalysis-chemistry, auxiliary class Metabolic Enzyme,ROR, name is (S)-3-(6-(3-(Difluoromethoxy)-5-fluorophenyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)-2,2-dimethylpropanoic acid, and the molecular formula is C38H74Cl2N2O4, Formula: C27H23F6NO6S.

Referemce:
https://courses.lumenlearning.com/boundless-chemistry/chapter/catalysis/,
Catalysis – Wikipedia

Heydari, Paniz published the artcileDevelopment and validation of an LC-MS/MS assay for the quantification of cintirorgon (LYC-55716) in mouse plasma and tissue homogenates, Quality Control of 2055536-64-4, the publication is Journal of Pharmaceutical and Biomedical Analysis (2022), 114421, database is CAplus and MEDLINE.

Cintirorgon (LYC-55716) is a promising first-in-class antitumor agent as a ROR¦Ã agonist in the treatment against various types of cancer. To support preclin. mouse studies, a bioanal. method was developed and successfully applied for quantification of cintirorgon in mouse plasma and tissue homogenates using LC-MS/MS. The method was fully validated in mouse plasma and partial validation was performed in eight different homogenates originating from brain, kidney, liver, lung, small intestine, small intestine content, spleen, and testis. Sample preparation was performed using 96-well plates for fast and efficient anal. Protein precipitation was done by addition of 20¦ÌL acetonitrile containing monensin as internal standard to 10¦ÌL sample. Chromatog. separation was achieved on a Polaris 3 C18-A column using gradient elution with 0.2% (volume/volume) formic acid and 0.2% (volume/volume) ammonium hydroxide in water (A) and methanol (B) as eluents. The total run time was 3 min. Detection was carried out with a triple quadrupole mass spectrometer with electrospray ionization operated in the pos. ion-mode. Quantification could be accomplished within a linear validated concentration range of 5-4,000 ng/mL (10-4,000 ng/mL in brain homogenates) with an intra- and inter-day precision between 4.6-14.7% and 5.1-15.6% (including the LLOQ), resp., and accuracies between 89.1%-111.2%. The method was successfully applied to a preclin. study with cintirorgon in mice.

Journal of Pharmaceutical and Biomedical Analysis published new progress about 2055536-64-4. 2055536-64-4 belongs to catalysis-chemistry, auxiliary class Metabolic Enzyme,ROR, name is (S)-3-(6-(3-(Difluoromethoxy)-5-fluorophenyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)-2,2-dimethylpropanoic acid, and the molecular formula is C27H23F6NO6S, Quality Control of 2055536-64-4.

Referemce:
https://courses.lumenlearning.com/boundless-chemistry/chapter/catalysis/,
Catalysis – Wikipedia

Li, Wenlong published the artcileABCB1 restricts brain accumulation of the novel ROR¦Ã agonist cintirorgon, while OATP1A/1B and CYP3A limit its oral availability, Application In Synthesis of 2055536-64-4, the publication is European Journal of Pharmaceutics and Biopharmaceutics (2022), 135-146, database is CAplus and MEDLINE.

Cintirorgon (LYC-55716), a first-in-class, small-mol., oral selective ROR¦Ã agonist, has been developed as a new immuno-oncol. drug for solid tumors. We here studied the functions of the ABCB1 and ABCG2 multidrug efflux transporters, the OATP1A/1B uptake transporters, and the drug-metabolizing CYP3A enzyme complex in cintirorgon pharmacokinetics using genetically modified mouse models. Cintirorgon was modestly transported by human ABCB1 and mouse Abcg2 in vitro. Upon oral administration at 40 mg/kg, net cintirorgon brain penetration was enhanced in Abcb1a/1b^-/- (2.1-fold) and Abcb1a/1b;Abcg2^-/- (2.7-fold) relative to wild-type mice. Deficiency of Oatp1a/1b led to a substantial (2.4-fold) increase in cintirorgon systemic exposure, with a corresponding (2.3-fold) decrease in hepatic distribution. However, these changes were not rescued in mice overexpressing human OATP1B1 or human OATP1B3 in liver, although this did partially reverse the altered cintirorgon glucuronide pharmacokinetics in Oatp1a/1b^-/- mice. In Cyp3a^-/- mice, the cintirorgon plasma AUC_0-8h was 1.4-fold increased, and then decreased by 1.5-fold upon overexpression of transgenic human CYP3A4 in intestine and liver. Cintirorgon brain accumulation was thus markedly restricted by ABCB1. Mouse Oatp1a/1b mediated cintirorgon uptake into the liver, thus limiting its plasma exposure. Moreover, oral availability of cintirorgon was limited by CYP3A. These insights could help optimizing cintirorgon¡äs clin. application.

European Journal of Pharmaceutics and Biopharmaceutics published new progress about 2055536-64-4. 2055536-64-4 belongs to catalysis-chemistry, auxiliary class Metabolic Enzyme,ROR, name is (S)-3-(6-(3-(Difluoromethoxy)-5-fluorophenyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)-2,2-dimethylpropanoic acid, and the molecular formula is C27H23F6NO6S, Application In Synthesis of 2055536-64-4.

Referemce:
https://courses.lumenlearning.com/boundless-chemistry/chapter/catalysis/,
Catalysis – Wikipedia