EGFR (IC50 = 7.4 nM); ErbB2 (IC50 = 9 nM)

Canertinib significantly inhibits the growth of RaH3 and RaH5 cultured melanoma cells, in a dose-dependent manner. After 72 hours of treatment, both cell lines completely stop growing at 5μM, with an IC50 of about 0.8 μM. When 1 μM canertinib was added to exponentially growing RaH3 and RaH5, the cells accumulated in the G1-phase of the cell cycle within 24 hours of treatment, without causing apoptosis. In both cell lines, 1 μM canertinib inhibits the phosphorylation of the ErbB1-3 receptor while concurrently lowering the activity of Akt, Erk1/2, and Stat3.
Canertinib also is a potent exosome secretion activator[3].

Canertinib exhibits better in vivo antitumor activity, causing growth delays in A431 xenografts that last longer than 50 days after oral administration[1]. Intraperitoneal injections of 40 mg/kg/day canertinib significantly inhibit the growth of human malignant melanoma xenografts, RaH3 and RaH5, in nude mice (Fig. 4). Observed through differences in tumor volumes, the anti-proliferative effect on melanoma xenografts is evident as early as day 4 of treatment and continues to increase over the course of the course of treatment, reaching statistical significance within 18 days of treatment[2].

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In Vivo Activity. [1]
The quinazolines 8 and 18/Canertinib and the pyrido[3,2-d]pyrimidine 25 were evaluated against A431 xenografts in mice, and the results are given in Table 3. Both 8 and 18/Canertinib showed impressive activity when dosed orally for 14 days, but the derivative 18 was much more potent (optimal dose 5 mg/kg/day) compared to the other analogues. The pyrido[3,2-d]pyrimidine 25 was only minimally effective, indicating a very low dose potency for this compared to both the other derivatives tested even though it was equally soluble. The essentially equivalent antitumor activity for 18 at the two dose levels shown in Table 3 suggests that this compound might have a good therapeutic index. Weight loss, as an indicator of compound-induced toxicity, was minimal in the experimental animals, being less than 10% at tolerated dose levels.

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Canertinib inhibits melanoma cell proliferation in vivo [2]
The growth of human malignant melanoma xenografts, RaH3 and RaH5, in nude mice was significantly inhibited by i.p. injections of 40 mg/kg/day canertinib (Fig. 4). The anti-proliferative effect on melanoma xenografts was visible already within 4 days of treatment and further increased throughout the treatment period as observed through the differences in tumor volumes, reaching statistical significance within 18 days of treatment (RaH3 P = 0.021 and RaH5 P = 0.014) (Fig. 4A and B). The growth inhibition of canertinib on RaH3 and RaH5 xenografts was also reflected by a significant decrease in tumor weights as compared to untreated tumors (Fig. 4C). The detectable side effects were mild including less than 8% weight loss in the treated mice compared to untreated animals, with no signs of skin rash, diarrhea or any other side effect, all animals seemed to thrive despite treatment. However, one RaH5 xenograft-bearing mouse died in the treatment group at day 5 without showing any signs of illness.

In 96-well filter plates, enzyme assays are carried out to determine IC50. 20 mM Hepes, pH 7.4, 50 mM sodium vanadate, 40 mM magnesium chloride, 10 µM adenosine triphosphate (ATP) containing 0.5 mCi of [³²P]ATP, 20 mg of polyglutamic acid/tyrosine, 10 ng of EGFR tyrosine kinase, and suitable dilutions of inhibitor (Canertinib) are all included in the 0.1 mL total volume. All ingredients are added to the well, with the exception of the ATP, and the plate is shaken for 10 minutes at 25°C. After adding [³²P]ATP, the plate is incubated for 10 minutes at 25°C to initiate the reaction. The addition of 0.1 mL of 20% trichloroacetic acid (TCA) stops the reaction. To enable the substrate to precipitate, the plate is maintained at 4°C for a minimum of 15 minutes. After that, 0.2 mL of 10% TCA and ³²P incorporation measured with a plate counter are used to wash the wells five times[1].

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Aqueous Stability Study of 18/Canertinib and 25. [1]
Stock solutions of the compounds in DMSO were diluted into phosphate buffers at pH 2.6, 6.67, and 10.75. The solutions were kept at 37 °C, and HPLC traces were made at time zero and at other time points out to 24 h. The peak areas of the parent drug and the amine hydrolysis product were calculated as a percent of the t = 0 value. The HPLC conditions were:  column, Zorbax SB-C18, 4.6 mm × 25 cm; mobile phase, 0.45 M formate buffer (ammonium formate + formic acid, pH 3.45), 80% acetonitrile, 20% MilliQ water; gradient elution, beginning aqueous/organic phase ratio 1:9, altering over 25 min to 100:0 and kept at 100:0 for another 5 min. Flow rate was 1.0 mL/min, and detection was by UV at 254 nm. Mass Spectrometry. Solutions of compounds 18/Canertinib and 25 in DMSO were added to a solution containing 25 μg of EGF receptor tyrosine kinase protein (in 20 mM Tris, 150 mM NaCl, 1 mM DTT, 1 mM EDTA) and small amounts of protease inhibitors aprotinin and leupeptin and diluted with 75 mM ammonium bicarbonate (pH 7.5). The reaction was quenched after 90 min upon addition of 5% (v/v) acetic acid, and the protein was purified and concentrated by centrifugal filtration. The molecular weight of the protein−drug complex in a denaturing solution (80% CH3CN, pH 2.5) was determined by ESI-MS equipped with a low-flow micro-ESI source operating at 150 nL/min. A portion of drug-bound protein was reduced, alkylated, and digested with trypsin. Peptides were eluted from the 0.3- × 15-mm Vydac C18 column directly into the mass spectrometer with a linear gradient of CH3CN at 5 γμL/min as follows:  5% solvent B to 95% solvent B over 10 min (where A = 0.05% TFA/2% CH3CN and B = 0.045% TFA/90% CH3CN).

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Tyrosine Kinase Assays. [1]
EGFR tyrosine kinase was purified as described previously. Enzyme assays for IC50[app] determinations were performed in 96-well filter plates. The total volume was 0.1 mL containing 20 mM Hepes, pH 7.4, 50 mM sodium vanadate, 40 mM magnesium chloride, 10 μM adenosine triphosphate (ATP) containing 0.5 mCi of [32P]ATP, 20 mg of polyglutamic acid/tyrosine, 10 ng of EGFR tyrosine kinase, and appropriate dilutions of inhibitor. All components except the ATP were added to the well and the plate was incubated with shaking for 10 min at 25 °C. The reaction was started by adding [32P]ATP, and the plate was incubated at 25 °C for 10 min. The reaction was terminated by addition of 0.1 mL of 20% trichloroacetic acid (TCA). The plate was kept at 4 °C for at least 15 min to allow the substrate to precipitate. The wells was then washed five times with 0.2 mL of 10% TCA and 32P incorporation determined with a Wallac beta plate counter.

Canertinib is applied to RaH3 and RaH5 cells at escalating concentrations (0–10 μM) for a duration of 72 hours. The cells are counted after being suspended in buffer[2].

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Irreversibility Test Protocol. [1]
A431 human epidermoid carcinoma cells were grown in 6-well plates to about 80% confluency and then incubated in serum-free media for 18 h. Duplicate sets of cells were treated with 2 mM of designated compound to be tested as an irreversible inhibitor for 2 h. One set of cells was then stimulated with 100 ng/mL EGF for 5 min and extracts made as described under the Western blotting procedure. The other set of cells was washed free of the compound with warmed serum-free media, incubated for 2 h, washed again, incubated another 2 h, washed again, and then incubated a further 4 h. This set of cells was then stimulated with EGF and extracts were made similar to the first set of cells.

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Western Blotting Procedure. [1]
Extracts were made by lysing cells in 0.2 mL of boiling Laemlli buffer (2% sodium dodecyl sulfate, 5% β-mercaptoethanol, 10% glycerol, and 50 mM tris[hydroxymethyl]aminomethane (Tris), pH 6.8), and the lysates were heated to 100 °C for 5 min. Proteins in the lysate were separated by polyacrylamide gel electrophoresis and electrophoretically transferred to nitrocellulose. The membrane was washed once in 10 mM Tris, pH 7.2, 150 mM NaCl, 0.01% azide (TNA), and blocked overnight in TNA containing 5% bovine serum albumin and 1% ovalbumin. The membrane was blotted for 2 h with antiphosphotyrosine antibody (UBI, 1 mg/mL in blocking buffer) and then washed twice in TNA, once in TNA containing 0.05% Tween-20 detergent and 0.05% nonidet P-40 detergent, and twice in TNA. The membranes were then incubated for 2 h in blocking buffer containing 0.1 mCi/mL [125I]protein A and then washed again as above. After the blots were dry, they were loaded into a film cassette and exposed to X-AR X-ray film for 1−7 days. Band intensities were determined with a Molecular Dynamics laser densitometer.

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Caco-2 Cell Permeability. [1]
The absorptive and secretory transport of compounds 18/Canertinib and 25 were carried out in Caco-2 cells.24 Apical-to-basolateral (A→B) and basolateral-to-apical (B→A) experiments were performed in side-by-side diffusion apparatus with 25 μM of drug. [14C]Mannitol was used to monitor cell integrity and [3H]metoprolol, which is 90−95% absorbed in human, 30,31 was used as a reference compound. Cells were at passage 35 or 21, 23 or 25 days post-seeding, with an average TEER measurement of 430−508. The incubation solutions were prepared in Hank's balanced salt solution (HBSS) with 2% ethanol and 2% DMSO; pH was 6.5 and 7.4, respectively, in apical and basolateral compartments. Bidirectional transport experiments of [3H]vinblastine were performed simultaneously for confirmation of P-gp activity.25,26 Drug concentrations were monitored using an LC−MS/MS method; reference compounds were measured using scintillation counting. [1]
The effect of 18/CanertinibCanertinib and 25 on P-glycoprotein transport was carried out using Caco-2 cells of passage 21, 21 days post-seeding with an average TEER measurement of 484. Apical-to-basolateral (A→B) and basolateral-to-apical (B→A) control experiments were performed in side-by-side diffusion apparatus with [3H]vinblastine in the donor compartment. The compounds (25 μM) were added to both apical and basolateral compartments in B→A experiments to examine its inhibitory effects on [3H]vinblastine efflux. Cyclosporin (10 μM) was also used as a positive control inhibitor,27,28 and [14C]mannitol was used to monitor cell integrity. The incubation solutions were prepared in Hank's balanced salt solution (HBSS) buffer (pH 6.5 apical, pH 7.4 basolateral) with 2% EtOH and 2% DMSO as cosolvents. [14C]Mannitol permeability values indicated that the cell monolayers remained viable throughout these studies.

Mice: Treatment with canertinib begins when tumors exhibit consistent growth. Groups for treatment and control are randomly assigned to the mice. Every mouse in the canertinib-treated RaH3 group (n = 4) and RaH5 group (n = 7) gets intraperitoneal injections five days a week of 1.2 mg canertinib (40 mg/kg/day) in 0.1 ml 0.15 M NaCl. The same regimen is followed for the intraperitoneal injection of vehicle only in the control RaH3 (n = 3) and RaH5 (n = 7) mice. The mice are sacrificed by cervical dislocation at the conclusion of the treatment period, following the removal and weighing of the tumors[2].

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In Vivo Chemotherapy. [1]
Immune-deficient mice were housed in microisolator cages within a barrier facility on a 12-h light/dark cycle and received food and water ad libitum. Animal housing was in accord with AAALAC guidelines. All experimental protocols involving animals were approved by the institutional animal care and use committee. The A431 epidermoid carcinoma was maintained by serial passage in nude mice (NCr nu/nu). Nude mice were also used as tumor host for anticancer agent evaluations against this tumor model. In each experiment, test mice weighing 18−22 g were randomized and implanted with tumor fragments in the region of the right axilla on day 0. Animals were treated with test compounds on the basis of average cage weight (6 mice/dose group) initiated when tumors reached approximately 100−150 mg in mass and continued for the period indicated in Table 3. Whenever possible test compounds were evaluated over a range of dose levels ranging from toxic to ineffective. [1]
The doses reported in Table 3 are the maximum doses that could be administered without exceeding the LD10, unless otherwise indicated. This maximum tolerated dose (MTD) allows comparisons to be made among the tested compounds at an equitoxic dose level. Derivatives 8 and 18/Canertinib were administered as solutions of the isethionate salt generated in situ by the addition of 1.5 equiv of aqueous isethionic acid followed by dilution to dosing volume with distilled water (final pH 4). Compound 25 was dissolved directly in 50 mM sodium lactate buffer, pH 4. Compound dosing solutions were prepared for 5 days at a time. Host body weight change data are reported as the maximum treatment-related weight loss in these studies. Calculations of tumor growth inhibition (% T/C) and tumor growth delay (T−C) were performed as described previously.

Pharmacokinetics [5]
This study used population pharmacokinetic analysis to evaluate plasma pharmacokinetic data from 43 patients and 29 patients from another phase I study. Patients in the phase I study received monthly dosing for 3 weeks. Pharmacokinetic analysis was performed using a single-compartment linear model: NONMEMV and ADVAN2. Peak concentrations of CI-1033 were reached 2 to 4 hours after dosing and were dose-dependent. The mean plasma clearance (Cl/F) was 266 L/h, the mean volume of distribution (Vd/F) was 1330 L, and the apparent plasma elimination half-life was 4 hours. No accumulation of CI-1033 was observed after repeated dosing, and no adverse events were associated with atypical systemic exposures in any dose group. Post-hoc analysis showed that systemic exposures were independent of age, sex, race, weight, or body surface area. These findings support the use of once-daily dosing in adult patients without adjustment based on weight or body surface area.

Safety [5] Adverse events reported during the first course of treatment included: diarrhea (25 cases, 47%); rash (29 cases, 55%); mucositis (17 cases, 32%); nausea (20 cases, 38%); vomiting (16 cases, 32%); allergic reactions, including urticaria, periorbital edema, glossitis, and asymptomatic wheezing (5 cases, 9%); thrombocytopenia (4 cases, 8%); and various other toxic reactions (Table 2). The number of grade 3 treatment-related toxicities (1 case of thrombocytopenia, 1 case of dehydration, and 1 case of nausea) in subsequent courses was small, indicating no significant cumulative toxicity, and no patients withdrew from the study due to treatment-related adverse events. In patients with multiple rashes, most rashes were of the same severity in the same patient, and no cases were reported to have worsened rashes after subsequent courses of treatment. The investigators described the rashes as acne-like or folliculitis-like rashes, and the frequency of rashes increased with increasing dose, consistent with reports of other ERGR inhibitors. Gastrointestinal toxicity was the most common adverse event during the study: diarrhea (62%), nausea (47%), mucositis (32%), and vomiting (30%). These adverse events were generally grade 1 to 2 and could be managed with early intervention and standard treatment. Hypersensitivity reactions occurred only in the high-dose group (≥560 mg). One patient receiving the 560 mg dose developed angioedema of the tongue, accompanied by urticaria and skin wheals 5 hours after administration. This patient did not experience respiratory symptoms, and this dose-limiting toxicity was effectively controlled with antihistamines, steroids, and dose reduction. A second patient in the 560 mg dose group experienced mild wheezing on days 4–5, which was considered to be related to underlying asthma. One patient in the 650 mg dose group experienced hand itching on day 1 and mild wheezing on days 5–7, without requiring dose reduction. Another patient in the 650 mg dose group experienced mild periorbital edema, urticaria, and chest tightness on day 1, which were relieved by antihistamine treatment.
Although thrombocytopenia is not a common clinical toxicity, laboratory data analysis showed that 22 patients (42%) experienced one or more platelet counts below normal: 16 patients were grade 1-2, 5 were grade 3, and 1 was grade 4. Two cases of thrombocytopenia were considered dose-limiting toxicities in both the 50 mg and 650 mg dose groups. The duration of thrombocytopenia was closely related to the duration of CI-1033 treatment. No clear dose-related or cumulative dose effect was observed, but more grade 1-2 events were recorded in the 350-750 mg dose groups (12 out of 26 patients, 47%). However, all five cases of grade 3 thrombocytopenia occurred in the lower dose group, which confounds the association between dose and the observed degree of thrombocytopenia.

[1]. Tyrosine kinase inhibitors. 17. Irreversible inhibitors of the epidermal growth factor receptor: 4-(phenylamino)quinazoline- and 4-(phenylamino)pyrido[3,2-d]pyrimidine-6-acrylamides bearing additional solubilizing functions. J Med Chem. 2000 Apr 6;43(7):1380-97.

[2]. The pan-ErbB receptor tyrosine kinase inhibitor canertinib promotes apoptosis of malignant melanoma in vitro and displays anti-tumor activity in vivo. Biochem Biophys Res Commun. 2011 Oct 28;414(3):563-8.

[3]. Mechanisms associated with biogenesis of exosomes in cancer. Mol Cancer. 2019 Mar 30;18(1):52.

[4]. Progress in the discovery of compounds inhibiting orthopoxviruses in animal models. Antivir Chem Chemother. 2008;19(3):115-24.

[5]. Phase I clinical and pharmacodynamic evaluation of oral CI-1033 in patients with refractory cancer. Clin Cancer Res. 2007 May 15;13(10):3006-14.

Cananatinib is a quinazoline compound with a 3-chloro-4-fluoroaniline group linked at position 4, an acrylamide group at position 6, and a 3-morpholinopropoxy group at position 7. It is a tyrosine kinase inhibitor and antitumor drug. It belongs to the quinazoline, organofluorine, morpholine, and monochlorobenzene classes. Cananatinib is a pan-ERB tyrosine kinase inhibitor, effective against esophageal squamous cell carcinoma both in vitro and in vivo. PET scans show that cananatinib treatment significantly affects tumor metabolism, proliferation, and hypoxia. Indications: It has been studied for the treatment of breast cancer and lung cancer. Mechanism of Action: CI-1033 effectively inhibits the growth of esophageal squamous cell carcinoma that simultaneously expresses EGFR and HER2, through the inhibition of MAPK and AKT phosphorylation. Some studies suggest that CI-1033 has significant clinical application potential in the treatment of esophageal cancer.

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4-Phenylinoquinazoline- and 4-Phenylinopyrido[3,2-d]pyrimidine-6-acrylamides with solubilizing 7-alkylamine or 7-alkoxyamine side chains were prepared by reacting the corresponding 6-amines with acrylic acid or acrylic anhydride. In the pyrido[3,2-d]pyrimidine series of compounds, the intermediate 6-amino-7-alkylamine was prepared by Stille coupling of 7-bromo-6-fluoropyrido[3,2-d]pyrimidine with the corresponding tinane under palladium(O) catalysis. This method has been shown to be a general approach for introducing cationic solubilizing side chains. These compounds were evaluated for their inhibitory effects on isolated EGFR enzyme phosphorylation, as well as on EGF-stimulated EGFR autophosphorylation in A431 cells and heregulin-stimulated erbB2 autophosphorylation in MDA-MB 453 cells. Quinazoline analogs with 7-alkoxyamine solubilizing groups are potent and irreversible inhibitors of isolated EGFR enzymes, with IC50 values of 2 to 4 nM, and effectively inhibit the autophosphorylation of EGFR and erbB2 in cells. 7-alkylamino and 7-alkoxyamino pyrido[3,2-d]pyrimidines are also irreversible inhibitors, exhibiting equal or stronger inhibitory efficacy against isolated enzymes, but showing poorer results in cellular autophosphorylation assays. As shown by electrospray ionization mass spectrometry, both quinazoline- and pyrido[3,2-d]pyrimidine-6-acrylamide can bind to ATP-binding sites, alkylate cysteine 773, and exhibit similar absorption and secretory transport rates in Caco-2 cells. A comparison of the two 7-propoxymorpholine analogs shows that pyrido[3,2-d]pyrimidine-6-acrylamide has higher amide instability, higher acrylamide reactivity, and is converted to glutathione adducts more rapidly in cells than the corresponding quinazoline. This difference may have led to the observed lower cellular activity of pyrido[3,2-d]pyrimidine-6-acrylamide compounds. Some compounds showed higher in vivo activity against A431 xenografts after oral administration, with quinazoline compounds being superior to pyrido[3,2-d]pyrimidine compounds. Overall, quinazoline compounds were superior to previous analogs in terms of water solubility, activity, and in vivo antitumor activity, and one of the compounds (CI 1033) has been selected for clinical evaluation. [1]

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The ErbB receptor family is considered a target for specific treatment of malignant melanoma tumors. This study investigated the effects of the pan-ErbB tyrosine kinase inhibitor cananatinib on the growth and survival of human melanoma cells in vitro and in vivo. Cananatinib significantly inhibited the growth of cultured melanoma cells RaH3 and RaH5 in a dose-dependent manner, as confirmed by cell counting results. The half-maximal inhibitory dose (IC50) was approximately 0.8 μM, and both cell lines completely stopped growing after 72 hours of treatment with 5 μM cananatinib. Flow cytometry analysis showed that RaH3 and RaH5 cells in the exponential growth phase were incubated with 1 μM canatinib, and the cell cycle was arrested in the G1 phase after 24 hours without inducing apoptosis. Immunoblotting analysis showed that 1 μM canatinib inhibited the phosphorylation of ErbB1-3 receptor in both cell lines, accompanied by a decrease in the activities of Akt, Erk1/2 and Stat3. In contrast to the cell inhibition observed with canatinib at concentrations ≤5 μM, higher concentrations of canatinib induced apoptosis, which was confirmed by Annexin V method and Western blot analysis of PARP lysis. In addition, canatinib significantly inhibited the growth of RaH3 and RaH5 melanoma xenografts in nude mice. Drug therapy targeting ErbB receptor may be effective for the treatment of patients with metastatic melanoma. [2]

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Communication between cells in the tumor and distant sites is crucial for the development and progression of cancer. Exosomes have become a potential regulator of intracellular communication in cancer. Exosomes are nanovesicles released by cells that contain biomolecules and are exchanged between cells. The exchange of exosomes between cells is involved in many processes that are crucial to tumor progression, and therefore, altering the release of exosomes is an attractive therapeutic target. This article reviews the current understanding of the mechanisms regulating exosome release in cancer and the knowledge gaps. [3]

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Alternative animal models must be used to test antiviral drugs against smallpox virus infection. Once developed, these compounds can be stockpiled for use in response to bioterrorism involving smallpox virus or monkeypox virus, or for the treatment of sporadic severe orthopox virus infections, such as disseminated cowpox complications following live virus vaccination. Significant progress has been made in recent years in the discovery of novel antiviral drugs that are effective against orthopox virus in vivo. This includes developing new animal models or improving existing models for testing the efficacy of compounds. Current mouse models use murine pox virus, cowpox virus, and cowpox virus (WR and IHD strains), and are typically used to study respiratory (lung) or tail lesions. Rabbitpox virus and cowpox virus (WR strain) can be used for rabbit infection studies. Monkeypox virus and smallpox virus are commonly used to infect monkeys. This review describes these and other animal models and covers active compounds found in vivo since 2003. Sidofovir was known to be effective against orthopox virus infection before 2003 and has been extensively studied in recent years. Some promising new compounds are oral-efficate orthopox virus infection inhibitors, including ether prodrugs of cidofovir and (S)-HPMPA, ST-246, N-methoxyacetamide thymidine (N-MCT), and SRI 21950 (a 4'-thio derivative of iododeoxyuridine). Another highly active compound that requires parenteral administration is HPMPPO-DAPy. Further development of these compounds is necessary. [4]

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Objective: To determine the tolerability and pharmacokinetics of CI-1033 administered daily for 7 days (21-day cycle). This study examined tumor response and changes in erbB receptor tyrosine kinase activity in tumor and skin tissues, and explored the regulation of potential biomarkers in plasma. Design: This was a dose-exploratory phase I study in patients with advanced solid malignancies. Patient safety, pharmacokinetics, and tumor response were assessed. Pharmacodynamic biomarkers, such as Ki67, p27, and erbB receptor status, in tumor and skin tissues were detected using immunohistochemistry and immunoprecipitation. Plasma biomarkers HER2, vascular endothelial growth factor, interleukin-8, and matrix metalloproteinase-9 were evaluated using immunological techniques. Results: A total of 53 patients were enrolled. Dose-limiting toxicities (vomiting, persistent rash, and oral ulcers) were observed at a dose of 750 mg. The maximum tolerated dose was 650 mg. No confirmed objective response was observed. CI-1033 treatment showed downregulation of epidermal growth factor receptor, HER2, and Ki67 in various tumor tissues, and upregulation of p27 in skin tissue. Plasma HER2 levels decreased after CI-1033 administration, but no significant changes were observed in vascular endothelial growth factor, interleukin-8, or matrix metalloproteinase-9. Plasma concentrations of CI-1033 were dose-dependent. Conclusion: The safety and pharmacokinetic characteristics of CI-1033 are favorable for multiple oral administrations. Regulation of erbB receptor activity in tumor and skin tissues is accompanied by changes in proliferation markers and cell cycle inhibition markers. More clinical trials are needed to clarify the role of CI-1033 in cancer treatment and to further evaluate the efficacy of antitumor markers. [5]

C24H25CLFN5O3

485.94

485.162

C, 59.32; H, 5.19; Cl, 7.30; F, 3.91; N, 14.41; O, 9.88

267243-28-7

Canertinib dihydrochloride;289499-45-2

156414

Light yellow to yellow solid powder

1.4±0.1 g/cm3

691.0±55.0 °C at 760 mmHg

188-190°

371.7±31.5 °C

0.0±2.2 mmHg at 25°C

1.650

3.65

2

8

9

34

671

0

ClC1=C(C([H])=C([H])C(=C1[H])N([H])C1C2=C([H])C(=C(C([H])=C2N=C([H])N=1)OC([H])([H])C([H])([H])C([H])([H])N1C([H])([H])C([H])([H])OC([H])([H])C1([H])[H])N([H])C(C([H])=C([H])[H])=O)F

OMZCMEYTWSXEPZ-UHFFFAOYSA-N

InChI=1S/C24H25ClFN5O3/c1-2-23(32)30-21-13-17-20(14-22(21)34-9-3-6-31-7-10-33-11-8-31)27-15-28-24(17)29-16-4-5-19(26)18(25)12-16/h2,4-5,12-15H,1,3,6-11H2,(H,30,32)(H,27,28,29)

N-[4-(3-chloro-4-fluoroanilino)-7-(3-morpholin-4-ylpropoxy)quinazolin-6-yl]prop-2-enamide

Canertinib; Canertinib free base; PD-183805; Canertinib; 267243-28-7; CI-1033; Canertinib (CI-1033); Canertinib free base; N-(4-(3-chloro-4-fluorophenylamino)-7-(3-morpholinopropoxy)quinazolin-6-yl)acrylamide; N-{4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(morpholin-4-yl)propoxy]quinazolin-6-yl}prop-2-enamide; N-[4-(3-chloro-4-fluoroanilino)-7-(3-morpholin-4-ylpropoxy)quinazolin-6-yl]prop-2-enamide; CI1033; CI1 033; CI-1033; PD 183805; PD183805

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: ≥ 1.25 mg/mL (2.57 mM) (saturation unknown) in 10% EtOH + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 12.5 mg/mL clear EtOH stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 1.25 mg/mL (2.57 mM) (saturation unknown) in 10% EtOH + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 12.5 mg/mL clear EtOH stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 1.25 mg/mL (2.57 mM) (saturation unknown) in 10% EtOH + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 12.5 mg/mL clear EtOH stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: 30% propylene glycol, 5% Tween 80, 65% D5W: 10mg/mL

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