RORγ

Compound 37c/Cintirorgon (LYC-55716) was evaluated further in a PK/PD assay. RORγt is highly expressed in the thymus and regulates the expression of genes important for the survival and development of thymocytes. The expression of RORγ target genes such as BclXL and Fbxo27 in thymus can be increased by RORγ agonists. Female C57/BL6 mice were dosed with vehicle (1% Tween 80) or RORγ agonist Cintirorgon (LYC-55716) (37c) at various doses and 6–16 h later, thymocytes were isolated, RNA was prepared and the expression of RORγ target genes was assayed using Q-PCR. Samples were collected contemporaneously for the determination of Cintirorgon (LYC-55716) plasma concentrations. The increase in RORγ target gene expression is plotted in Figure 3 versus plasma concentration and the data fitted to obtain an EC50 for 37c of 338 nM (95% confidence interval = 202–564 nM). [2]

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Select RORγ agonists were also evaluated in mouse syngeneic tumor models. Cell lines derived from murine tumors, either spontaneous or chemically induced, and reimplanted into immunologically competent mice have been used to evaluate other immunotherapies. In our mouse colorectal adenocarcinoma (MC38) tumor model, MC38 tumor cells were implanted subcutaneously into the flank of female C57/BL6 mice. Agonist treatment was initiated 3 days post-tumor implant and continued twice daily by oral gavage. Figure 4 illustrates the results from tumor-bearing mice treated with vehicle or 37c (30 mg/kg, bid). This study demonstrated a 46% inhibition in tumor growth (p < 0.05). The study was repeated two additional times with similar reductions of tumor growth (49 and 63%, p < 0.05). Tumor weights were evaluated at the end of the study. A similar reduction of tumor weight was also observed. The compound was well tolerated in all studies with no adverse effect on animal weights. Compounds 37c and 17 also inhibited tumor growth in a 4T1 breast tumor model. [2]

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Cintirorgon (LYC-55716) , a RORγ agonist, is administered orally and forms a receptor complex with the nuclear receptor transcription factor RORγ. The drug then translocates to the nucleus where it binds to the ROR response element (RORE) to improve function. Type 17 T cells, such as Th17 (helper T cells) and Tc17 (cytotoxic T cells), proliferate and survive. Th17/Tc17 differentiation is facilitated by the nuclear receptor transcription factor RORγ, which is also essential for immune activation. While next generation immuno-oncology medications, such as PD-1/PD-L1 inhibitors, are provided by injection, Cintirorgon (LYC-55716) is also bioavailable when taken orally [1].

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Pharmacodynamics[3]
The pharmacodynamics/target engagement assay assessed both the mRNA and protein expression of known RORγ target genes: IL-17A, IL-17F, and IL-22 following an ex vivo stimulation (19, 20). The modulation of these genes by RORγ agonists was confirmed in in vitro work with both healthy volunteer and cancer patient peripheral blood mononuclear cells (PBMC) and blood (22). As detailed above, blood samples were collected from all patients at various time points on days 1, 2, and 15 and shipped to a central laboratory for testing. Pharmacodynamic profiles for all analytes showed considerable intra- and inter-patient variability with regard to fold induction, absolute titer of cytokine, and timing of PDmax (see Supplementary Table S2 and representative data shown in Supplementary Fig. S2). The variability observed was not unexpected, given the patient-specific differences in baseline levels of RORγ expression and endogenous RORγ agonists (Supplementary Fig. S3; ref. 23). A formal PK/PD analysis was complicated both by the variability in the magnitude of each patient's response as well as the paucity of samples with plasma concentrations below the exposure associated with target gene modulation in rodents. However, pharmacodynamic data indicated that target engagement had occurred and provided qualitative evidence of a pharmacodynamic response, evidenced by post-treatment increases in cytokine production (Fig. 2A). In addition, 31 of the 32 patients showed greater than 2-fold induction for at least 1 of the pharmacodynamic readouts, which is consistent with the pharmacokinetic evidence for Cintirorgon (LYC-55716) exposure levels in the predicted efficacious range.

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Efficacy[3]
Of the 32 patients in the study, 25 were evaluable for response. Seven were not evaluable because of progressive disease within 6 weeks (n = 4), patient withdrawal (n = 2), and AE (n = 1). Of the evaluable patients, 2 (8%) achieved partial response and 11 (44%) achieved stable disease for a range of 2 to 12 months. Both of the partial responders and 6 (24%) of the patients with stable disease received >4 months of treatment with Cintirorgon (LYC-55716) (Fig. 3). One partial response was noted in a patient with non–small cell lung cancer [NSCLC; adenocarcinoma; PD-L1 tumor-proportion score (TPS) >50%] who had received first-line treatment with pembrolizumab (4 cycles, progression at first assessment), followed by carboplatin/pemetrexed (3 cycles, progression at first assessment) before entering the study (Fig. 4A). The time to initial response was approximately 6 months from the start of treatment; partial response was confirmed by independent central radiology review. A second partial response, also confirmed by independent central radiology review, was noted in a patient with sarcomatoid breast cancer (metastatic spindle cell carcinoma) who had received first-line treatment with carboplatin/paclitaxel (3 cycles, progression at first assessment), followed by gemcitabine/docetaxel (progression after 6 cycles) before the study (Fig. 4B). In this patient, the time to initial response was 8 months, following an incremental reduction in tumor burden before that point. Two patients remain on treatment as of June 2018: The patient with sarcomatoid breast cancer with partial response and a patient with endometrial cancer who has had disease stabilization for 9 months. Twelve (48%) patients had progressive disease as their best response. Two patients with colorectal cancer were followed under irRECIST after first assessment through discontinuation for progression at the end of 4 cycles.

Biological Assays for Agonist Activity Towards ROR [2]
Compounds were tested for ability to increase ROR activity using (i) a ROR-Ligand Binding Domain (LBD) TR-FRET Assay, and (ii) a Gal4-RORγ Luciferase Reporter Assay in HEK-293T Cells. Assay procedures are described below.

(i) Procedures for ROR-Ligand Binding Domain TR-FRET Assay [2]
HIS-tagged ROR-LBD protein was expressed in SF9 cells using a baculovirus expression system. The lysate was diluted in assay buffer (50 mM Tris pH 7.0, 50 mM KCl, 1 mM EDTA, 0.1 mM DTT, 0.01% BSA) to obtain ROR-LBD final concentration of ~3 nM in a 384-well assay plate (need to titrate for each batch of protein). A stock of biotinylated-LXXLL peptide from coactivator SRC1 (BiotinCPSSHSSLTERHKILHRLLQEGSPS) was prepared in assay buffer and added to each well (200 nM final concentration). A solution of Europium tagged anti-HIS antibody (0.6 nM final concentration) and APC-conjugated streptavidin (30 nM final concentration) were also added to each well. ROR antagonist ursolic acid was also included at a final concentration of 2 µM. Compounds were diluted in DMSO and further diluted in assay buffer with a final DMSO concentration at 1%. The highest concentration of test compound analyzed was 10 µM. [2]
The final assay mixture was incubated overnight at 4 °C or 2 hours at room temperature, and the fluorescence signal was measured on an Envision plate reader: (Excitation filter = 340 nm; APC emission = 665 nm; Europium emission = 615 nm; dichroic mirror = D400/D630; delay time = 100 µs, integration time = 200 µs). 50% Effective concentration (EC50) values for test compounds were calculated from the quotient of the fluorescence signal at 665 nm divided by the fluorescence signal at 615 nm. The quotient of the fluorescence signals in the absence of ursolic acid or test compound is set as 100. Max Response is defined as the upper plateau in the signal as determined by line-fit using a 4-parameter logistic model in PRISM. [2]

(ii) Procedures for Gal4-RORγ Luciferase Reporter Assay in HEK-293T Cells [2]
Transfection of HEK-293 Cells In the following protocol, HEK-293 cells were transfected with a construct comprising the Gal4 DNA binding domain fused to the ligand binding domain of RORγ (Gal4-RORγ-LBD) in a pcDNA3.1neo plasmid, and also with a reporter construct comprising pGL4.31 Gal4-luciferase. Control cells were prepared similarly using empty pcDNA3.1neo and pGL4.31 vectors. Trans-IT reagent (60 µL) at room temperature was added drop wise to OptiMEM (Invitrogen, 1.5 ml). This reagent mixture was mixed by inversion then incubated for 5 to 30 minutes at room temperature. It then was added to a solution of both expression vectors (5 µg each), mixed, and incubated at room temperature for about 20 minutes. HEK-293 cells were harvested from incubation flasks by removing the media, treating with TrypLE Express, and incubating until the cells detached from the bottom of the flask (approximately 2-5 minutes). 10 Million cells were collected by centrifugation and re-suspended in 10 mL of Dulbecco’s Modified Eagle Medium, High Glucose containing 10% Fetal Bovine Serum and 100 IU each of penicillin and streptomycin. The re-suspended cells and the S22 transfection mixture were added to a T75 flask, mixed and incubated overnight at 37 °C and 5% CO2.

Cellular Assay for RORγ Activity [2]
The cells were harvested as described above, counted, and centrifuged to obtain the desired number of cells, then re-suspended in complete growth media at 0.75 x 106 cells/mL. The RORγ antagonist, ursolic acid, was added to the cells at a final concentration of 2 µM. Cells were plated at 20 µL of cell suspension/well (10,000-15,000 cells/well) in white tissue culture treated 384 well plates. Test compounds were dissolved at 10 mM in DMSO then diluted into complete growth medium to 5x the final intended test concentration. These drug stock solutions, 5 µL/well were added to the tissue culture plate. The final DMSO concentration was 0.2%. The plates were briefly centrifuged then incubated overnight at 37 °C and 5% CO2. To conduct the assay, the tissue culture plates were allowed to equilibrate to room temperature and One-Glo luciferase reagent (5 µL/well) was added. The plates were briefly centrifuged then incubated at room temperature for 10 minutes. The luciferase intensity was read on an Envision plate reader. RORγ activity was determined relative to controls and plotted as a function of test compound concentration using PRISM to determine a 50% effective concentration (EC50). The luciferase signal in the absence of ursolic acid or test compound is defined at 100. The Max Response is the upper plateau in the signal as determined by line-fit using a 4-parameter logistic model in PRISM.

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Human Whole Blood Assay Method [2]
Briefly, human whole blood was collected into sodium-heparin tubes and T cell activators were added. Compound was added and samples were incubated 18 to 22 hours at 37 °C with 5% CO2. RNA was purified by Trizol/chloroform and RNeasy kits then used for RT-PCR and qPCR. S23  Dilution Ranges Tested of compounds 10, 3, 1, 0.3, 0.1, 0.03, 0 µM Procedures Assay and T cell Stimulation Conditions  Collect fresh blood in Sodium-Heparin tubes (50 mL)  Mix T cell activators with blood under 3 conditions:  Activator-1: Dynabeads human T-Activator CD3/CD28 at 15 µL/mL final; IL-1β, and IL23 final at 25 ng/mL final;  Activator-2: add soluble anti-CD3 and anti-CD28 final at 1 µg/mL final, IL-1β, and IL-23 at 10 ng/mL final  Activator-3: add PMA at 10 ng/mL and Ionomycin at 1 µg/mL final  Add 5 µL of 1000x drug stock or DMSO to 5 mL activated blood. The final DMSO concentration is 0.1%.  Aliquot 1.5 mL of blood per well in a 12-well tissue culture plate for triplicates  Incubate at 37°C with 5% CO2 for 18 to 22 hours

Pharmacodynamic Assay [2]
Retinoic acid receptor-related orphan receptor gamma (RORγ) is a transcription factor associated with thymocyte differentiation and maturation, as well as with Type 17 T cell differentiation and function. Activation of RORγ enhances thymocyte survival and induces a transcriptional program which drives Type 17 immune responses and decreases immune suppressive mechanisms. Small molecule agonists of RORγ modulate the expression of target genes including those involved in pro-survival pathways in thymocytes and release of cytokines and chemokines by mature immune cells. In the study, female C57BL/6 mice were given single oral doses of Cintirorgon (LYC-55716) ranging from 3 to 100 mg/kg and euthanized after 6, 10, or 16 hours (n of 4, 5, or 10 animals/time point or dose group). Thymi were collected as a tissue harboring high percentage of RORγ+ cells, RNA was extracted and expression of select RORγ target genes (Fbxo27, Xkrx, ReverbA, BclXL) was S26 analyzed via real-time quantitative polymerase chain reaction (qPCR) to determine the pharmacodynamic (PD) effects of Cintirorgon (LYC-55716) . Plasma samples were also collected at the same time thymi were taken and Cintirorgon (LYC-55716) concentration was determined. Fbxo27 showed the most consistent and robust window of induction following Cintirorgon (LYC-55716) treatment, and thus was used in determining the half-maximal effective concentration (EC50) of Cintirorgon (LYC-55716) . Based on Fbxo27 induction, the EC50 of LYC 55716 is 204 ng/mL (338 nM).

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Syngeneic Tumor Models [2]
MC38 murine colon carcinoma cells or 4T1 murine breast carcinoma cells were implanted subcutaneously into the flank of C57/BL6 or Balb/c mice, respectively. Three days after implantation, mice were dosed with vehicle (1% Tween 80) or test compound at doses noted in text twice a day. Tumor volume, measurable 10–12 days after implantation, was assessed two to three times weekly using caliper measurement of length and width of tumor. Tumor volume calculation = 0.5 x (length x (width)2 ). SCID.beige mice were also used as host mice for MC38 tumor cells to determine the immune system dependence. Mice were taken down after tumor volume reached ethical end point of 2,000 mm3 or at 24 day

Pharmacokinetics [3]
In this study, robust pharmacokinetic sampling was performed over several days during cycle 1. At steady state (day 29), drug exposure increased linearly from the lowest dose of 150 mg BID to the highest dose of 450 mg BID, with overlap at doses of 150 mg and 300 mg BID (Supplementary Table S1). The terminal concentrations in the once-daily dosing group were sufficient to determine that the plasma elimination half-life of Cintirorgon (LYC-55716) was approximately 13 hours (range 8–23 hours; data archived).
Using the regulation of RORγ-dependent gene expression in the mouse thymus as a preclinical PK/PD model, the 50% and 90% effective concentrations (EC50 and EC90) were determined to be 204 ng/mL and 1777 ng/mL, respectively (data archived). In all cohorts, among patients (n = 27) with available pharmacokinetic data on day 29, 100% had a Cmax exceeding EC50 and 93% exceeded EC90. Regarding Cmin values on day 29, 93% of patients exceeded EC50 and 44% exceeded EC90. Under the 450 mg BID dosing regimen (cohort 5), the median lowest plasma drug concentration (Cmin) exceeded EC50 by approximately 22 times and EC90 by approximately 2.5 times. The lowest plasma drug concentration was consistently higher with the twice-daily dosing regimen than with the once-daily dosing regimen, thus better covering the EC50 and EC90 targets (Figure 2B). Further characterization of Cintirorgon (LYC-55716) (37c) revealed selective activation of RORγ, while having no significant effect on other nuclear receptors, including RORα and RORβ (both with EC50 > 10 μM). This compound did not exhibit genotoxicity, and in patch-clamp assays, its IC20 against human ether-a-go-go-related potassium channels (hERG) was > 50 μM. It showed no inhibitory activity against major cytochrome P450 (CYP) isoenzymes (2D6, 3A4, 2C19), excellent metabolic stability, and moderate plasma protein binding (96.7% in mice; 98.6% in humans). Single-dose pharmacokinetic studies were conducted on the 37c sodium salt in male and female Sprague Dawley rats (1 mg/kg intravenously, 30, 100, and 300 mg/kg orally in male rats, and 100 mg/kg orally in female rats). Oral bioavailability was high (≥100%). Following intravenous injection, the half-life was 2.8 hours, with high clearance (48 mL/min/kg at 2.8 hours) and a high volume of distribution (Vd) (5.7 L/kg). Single-dose pharmacokinetic studies of the 37c sodium salt were also conducted in male cynomolgus monkeys (1 mg/kg intravenously, 10, 30, and 100 mg orally). Oral bioavailability was good (≥100%), with a half-life of 6.6 hours and moderate clearance (6.6 hours, 7.49 mL/min/kg). Volume of distribution (Vd) was moderate (1.42 L/kg). AUC values were similar in single-dose and multi-day studies. These results provided confidence for conducting GLP toxicology studies and ultimately led to the selection of LYC-55716 (Cintirorgon, 37c) as a candidate for clinical development. [2]

Safety and Tolerability [2] LYC-55716 was generally well tolerated, with most treatment-related adverse events being grade 1-2 (Table 2). No grade 4 treatment-related adverse events occurred. Grade 3 treatment-related adverse events included anemia (n = 2, occurring at weeks 7 and 10, respectively), elevated gamma-glutamyl transferase (n = 1, occurring at week 3), and hypophosphatemia (n = 1, 3 independent events, occurring at week 4). No patients required dose reduction during the study. A total of 6 patients experienced dose interruptions, none of which were due to treatment-related adverse events. Two patients in group 4a withdrew from the study due to adverse events: one withdrew due to fatigue (grade 2; possibly treatment-related) and weight loss (grade 2; not treatment-related), and one withdrew due to disease progression, which was recorded as "withdrawal due to adverse event".

[1]. Lycera Announces Initiation of Phase 1/2a Study ARGON of Immuno-Oncology Candidate LYC-55716 in Patients with Advanced Solid Tumors. Jan 04, 2017.

[2]. Discovery of LYC-55716: A Potent, Selective, and Orally Bioavailable Retinoic Acid Receptor-Related Orphan Receptor-γ (RORγ) Agonist for Use in Treating Cancer. J Med Chem. 2021 Sep 23;64(18):13410-13428.

[3]. Phase 1 Open-Label, Multicenter Study of First-in-Class RORγ Agonist LYC-55716 (Cintirorgon): Safety, Tolerability, and Preliminary Evidence of Antitumor Activity. Clin Cancer Res. 2019 Jun 15;25(12):3508-3516.

Cintellogen is an orally bioavailable retinoic acid-associated orphan receptor gamma (RORγ) agonist with potential immunomodulatory and antitumor activities. After oral administration, cintellogen selectively binds to the nuclear receptor transcription factor RORγ, forming a receptor complex. This complex translocates to the nucleus and binds to the ROR response element (RORE), thereby enhancing the function, proliferation, and survival of type 17 T cells, including Th17 helper T cells and Tc17 cells. This may increase the expression of co-stimulatory molecules on T cells and decrease the expression of co-inhibitory molecules, leading to increased production of cytokines and chemokines by T cells, reduced proliferation of regulatory T cells (Tregs), and elimination of tumor-induced immunosuppression. Ultimately, this induces a T cell-mediated immune response against cancer cells, resulting in reduced tumor cell growth. RORγ is a nuclear receptor transcription factor involved in Th17/Tc17 differentiation and plays a crucial role in immune activation. CINTIRORGON is a small molecule drug that has completed Phase I clinical trials (covering all indications) and has two investigational indications.

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New York and Ann Arbor, Michigan, January 4, 2017 /PRNewswire/ -- Lycera Corp., a privately held biopharmaceutical company developing breakthrough immunomodulatory drugs, today announced that its novel immuno-oncology drug candidate LYC-55716 has initiated a Phase I/IIa clinical trial for the treatment of patients with advanced, relapsed, or refractory solid tumors. “We continue to make rapid and significant progress in the development of novel immunomodulators. This is Lycera’s third clinical trial initiated in the past 12 months and our first immuno-oncology compound to enter clinical trials,” said Paul Sekhri, President and CEO of Lycera. “The positive results from our preclinical program demonstrate that LYC-55716 can modulate gene expression of RORγ-expressing T lymphocytes, thereby enhancing effector function and reducing immunosuppression, ultimately inhibiting tumor growth and improving survival in preclinical models in vivo. This process of reprogramming immune cells differs from other currently approved immunotherapies, and based on this, and the drug’s orally administered nature, we believe LYC-55716 holds the potential to be a major breakthrough for patients,” said John Nemunettis, Director and Principal Investigator at the Mary Crowley Medical Center in Dallas. “Unlike many immunotherapies that stimulate the immune system or reduce immunosuppression, Lycera’s RORγ agonist has been shown in preclinical models to simultaneously enhance T cell function and reduce immunosuppressive mechanisms. Oral RORγ agonist therapy may exhibit monotherapy efficacy and show synergistic effects when used in combination with other immunotherapies.” TX “We are delighted to collaborate with Lycera and jointly develop this compound with a novel mechanism of action.” The ARGON trial (a trial of the RORγ agonist LYC-55716 for advanced cancer) is a Phase 1/2a study of LYC-55716 in patients with advanced, relapsed, or refractory solid tumors. The initial Phase 1 portion of the study aims to determine the bioactive dose or maximum tolerated dose of LYC-55716. The study will employ a 3+3 study design, meaning patients with relapsed or refractory solid tumors will receive oral LYC-55716. The primary endpoint is safety and tolerability, and the study aims to determine the maximum tolerated dose (MTD) and the recommended dose for Phase 2. After dose determination, LYC-55716 will proceed to Phase 2a, with an expected enrollment of approximately 40 patients. The primary efficacy endpoint for the Phase 2a portion of the study is the objective response rate (ORR) as assessed according to the Evaluation Criteria in Solid Tumor Response (RECIST). About LYC-55716: LYC-55716 is a first-in-class oral selective RORγ agonist. Retinoic acid-associated orphan receptor γ (RORγ) is a nuclear receptor transcription factor that acts as a master switch for immune cells. RORγ agonists reprogram immune cells by modulating gene expression, thereby enhancing their function and reducing immunosuppressive mechanisms, ultimately suppressing tumor growth and prolonging survival in preclinical cancer models in vivo. Essentially, Lycera’s RORγ agonist strategy “removes the brakes on immune function” and “accelerates the performance of immune function.” [1] Retinoic acid receptor-associated orphan receptor γ (RORc, RORγ, or NR1F3) is a nuclear receptor master transcription factor that drives the function and development of IL-17-producing helper T cells (Th17), cytotoxic T cells (Tc17), and some intrinsic lymphocytes. Activation of RORγ+ T cells in the tumor microenvironment is thought to enhance the ability of immune infiltration to combat tumor growth. To verify this hypothesis, researchers optimized a class of benzoxazine compounds and finally obtained LYC-55716 (37c), a highly effective, selective, and orally bioavailable small molecule RORγ agonist. LYC-55716 was nominated as a clinical development candidate for patients with solid tumors because it inhibited tumor growth and prolonged survival in preclinical tumor models. [2]

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Objective: The transcription factor retinoic acid receptor-associated orphan receptor γ (RORγ) regulates the differentiation and function of type 17 effector T cells and is key to immune cell regulation. Synthetic RORγ agonists enhance effector T cell activity and reduce immunosuppression by regulating immune cell gene expression. A phase I study evaluated the safety and tolerability of LYC-55716 (cintirorgon), a first-in-class orally administered small molecule RORγ agonist, in adult patients with relapsed/refractory metastatic cancer. Patients and methods: Patients received oral LYC-55716 for 28 days; the dosage and administration regimen were determined based on pharmacokinetic characteristics and safety. The primary endpoints were safety and tolerability. Secondary endpoints included pharmacokinetics and objective tumor response rate. Results: 32 enrolled patients received LYC-55716 at doses ranging from 150 mg to 450 mg BID, with no dose-limiting toxicities. Treatment-related adverse events (AEs) were predominantly grade 1–2, including diarrhea (n = 11), fatigue (n = 7), anemia (n = 4), decreased appetite (n = 4), and nausea (n = 4). Grade 3 AEs included anemia (n = 2), elevated gamma-glutamyl transferase (n = 1), and hypophosphatemia (n = 1). Pharmacokinetic concentrations met the expected levels for target gene regulation. Pharmacodynamic results indicated activation of the RORγ pathway. Two patients (non-small cell lung cancer and sarcomatoid breast cancer) achieved confirmed partial remission; 11 patients remained stable for 2 to 12 months (6 of whom received more than 4 months of treatment). Conclusion: These data support the safety and tolerability of LYC-55716 and support the selection of a 450 mg BID dose for a phase 2a study to evaluate the clinical activity, safety and biomarkers of LYC-55716 in patients with non-small cell lung cancer, head and neck cancer, gastric and esophageal cancer, renal cell carcinoma, urothelial carcinoma and ovarian cancer. [3]

C27H23F6NO6S

603.530047655106

603.115

C, 53.73; H, 3.84; F, 18.89; N, 2.32; O, 15.91; S, 5.31

2055536-64-4

2055538-47-9 (sodium);2055536-64-4 (free acid);

124126348

White to off-white solid powder

6.8

1

13

8

41

1020

1

O=C(O)C(C)(C)C[C@@H]1OC2=CC=C(C3=CC(F)=CC(OC(F)F)=C3)C=C2N(S(=O)(C4=CC=CC(C(F)(F)F)=C4)=O)C1

GULSIMHVQYBADX-FQEVSTJZSA-N

InChI=1S/C27H23F6NO6S/c1-26(2,24(35)36)13-20-14-34(41(37,38)21-5-3-4-17(11-21)27(31,32)33)22-10-15(6-7-23(22)39-20)16-8-18(28)12-19(9-16)40-25(29)30/h3-12,20,25H,13-14H2,1-2H3,(H,35,36)/t20-/m0/s1

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2.5 mg/mL (4.14 mM) (saturation unknown) in 5% DMSO + 40% PEG300 +5% Tween-80 + 50% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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 (Please use freshly prepared in vivo formulations for optimal results.)