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]
Plasma pharmacokinetics was evaluated using population pharmacokinetic analysis on data from the 43 patients in this study combined with data from 29 patients in a second phase I study where patients were dosed once weekly for 3 weeks every month. Pharmacokinetic analysis was done using a one-compartment linear model: NONMEMV and ADVAN2. Peak CI-1033 concentrations were achieved 2 to 4 h after dosing and were dose proportional. Plasma clearance (Cl/F) averaged 266 L/h, whereas the volume of distribution (Vd/F) averaged 1,330 liters, resulting in an apparent plasma elimination half-life of 4 h. CI-1033 did not accumulate with repeated dosing, and there was no evidence to suggest that adverse events were associated with atypical systemic exposure within dose groups. Post hoc analysis suggested that systemic exposure is not dependent upon age, gender, race, weight, or surface area. These findings support once a day dosing without adjustment for body weight or surface area in adult patients.

Safety [5]
A summary of adverse events reported during course 1 included diarrhea (25 patients, 47%); rash (29 patients, 55%); mucositis (17 patients, 32%); nausea (20 patients, 38%); vomiting (16 patients, 32%); allergic reactions, including hives, periorbital edema, tongue edema, and asymptomatic wheezing (5 patients, 9%); thrombocytopenia (4 patients, 8%); and a miscellany of other toxicities (Table 2). There were no obvious cumulative toxicities as evidenced by the small number of grade 3 treatment-associated toxicities (1 thrombocytopenia, 1 dehydration, and 1 nausea) in subsequent cycles, and no patients discontinued the study due to treatment-related adverse events. Of those patients experiencing multiple events of rash, most were considered of the same intensity within a patient, and none were reported as worsening following additional courses. Investigator descriptions of rash were consistent with an acneiform or follicular appearance that increased in frequency at higher dose levels consistent with reports from other ERGR inhibitors. Gastrointestinal toxicities were the most predominant adverse events during the study: diarrhea (62%), nausea (47%), mucositis (32%), and vomiting (30%). These events were generally of grade 1 to 2 intensity and were manageable with early intervention and standard treatment.

Hypersensitivity reaction was not evident until the higher dose levels (≥560 mg). One patient at the 560 mg dose level experienced angioedema of the tongue accompanied by urticaria and skin welts 5 h post-dose. There were no respiratory manifestations, and this DLT was effectively managed with antihistamine, steroids, and dose reduction. A second patient in the 560 mg dose group experienced mild wheezing on days 4 to 5 that was considered related to underlying asthma. At the 650 mg dose level, one patient experienced pruritis of the hands on day 1 and mild wheezing on days 5 to 7 that did not require dose reduction. Another patient at 650 mg experienced mild periorbital edema, hives, and chest tightness on day 1 that was successfully treated with antihistamine.

Although thrombocytopenia was not frequently reported as a clinical toxicity, an analysis of platelet levels from laboratory data showed that one or more below normal readings were noted in 22 patients (42%): grade 1 to 2 in 16 patients, grade 3 in 5 patients, and grade 4 in 1 patient. Thrombocytopenia was considered dose limiting in two separate cases at 50 and 650 mg. The duration of thrombocytopenia coincided closely with the duration of CI-1033 treatment. There was no clear evidence of a dose relationship or a cumulative dose effect, but more grade 1 to 2 events (12 of 26 patients, 47%) were recorded at doses 350 to 750 mg. However, all five episodes of grade 3 thrombocytopenia occurred in the lower dose cohorts, confounding the association of dose with 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.

Canertinib is a quinazoline compound having a 3-chloro-4-fluoroanilino group at the 4-position, a propenamido group at the 6-position, and a 3-morpholinopropoxy group at the 7-position. It has a role as a tyrosine kinase inhibitor and an antineoplastic agent. It is a member of quinazolines, an organofluorine compound, a member of morpholines and a member of monochlorobenzenes.
Canertinib is a pan-erbB tyrosine kinase inhibitor which work against esophageal squamous cell carcinoma in vitro and in vivo. Canertinib treatment significantly affects tumour metabolism, proliferation and hypoxia as determined by PET.

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Drug Indication
Investigated for use/treatment in breast cancer and lung cancer.

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Mechanism of Action
CI-1033 effectively inhibits the growth of esophageal squamous cell carcinoma which co-expresses both EGFR and HER2 with the inhibition of phosphorylation of both MAPK and AKT. Some studies suggest that CI-1033 holds significant clinical potential in esophageal cancer.

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4-Anilinoquinazoline- and 4-anilinopyrido[3,2-d]pyrimidine-6-acrylamides substituted with solubilizing 7-alkylamine or 7-alkoxyamine side chains were prepared by reaction of the corresponding 6-amines with acrylic acid or acrylic acid anhydrides. In the pyrido[3,2-d]pyrimidine series, the intermediate 6-amino-7-alkylamines were prepared from 7-bromo-6-fluoropyrido[3,2-d]pyrimidine via Stille coupling with the appropriate stannane under palladium(0) catalysis. This proved a versatile method for the introduction of cationic solubilizing side chains. The compounds were evaluated for their inhibition of phosphorylation of the isolated EGFR enzyme and for inhibition of EGF-stimulated autophosphorylation of EGFR in A431 cells and of heregulin-stimulated autophosphorylation of erbB2 in MDA-MB 453 cells. Quinazoline analogues with 7-alkoxyamine solubilizing groups were potent irreversible inhibitors of the isolated EGFR enzyme, with IC(50[app]) values from 2 to 4 nM, and potently inhibited both EGFR and erbB2 autophosphorylation in cells. 7-Alkylamino- and 7-alkoxyaminopyrido[3,2-d]pyrimidines were also irreversible inhibitors with equal or superior potency against the isolated enzyme but were less effective in the cellular autophosphorylation assays. Both quinazoline- and pyrido[3,2-d]pyrimidine-6-acrylamides bound at the ATP site alkylating cysteine 773, as shown by electrospray ionization mass spectrometry, and had similar rates of absorptive and secretory transport in Caco-2 cells. A comparison of two 7-propoxymorpholide analogues showed that the pyrido[3,2-d]pyrimidine-6-acrylamide had greater amide instability and higher acrylamide reactivity, being converted to glutathione adducts in cells more rapidly than the corresponding quinazoline. This difference may contribute to the observed lower cellular potency of the pyrido[3,2-d]pyrimidine-6-acrylamides. Selected compounds showed high in vivo activity against A431 xenografts on oral dosing, with the quinazolines being superior to the pyrido[3,2-d]pyrimidines. Overall, the quinazolines proved superior to previous analogues in terms of aqueous solubility, potency, and in vivo antitumor activity, and one example (CI 1033) has been selected for clinical evaluation.[1]

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The ErbB receptor family has been suggested to constitute a therapeutic target for tumor-specific treatment of malignant melanoma. Here we investigate the effect of the pan-ErbB tyrosine kinase inhibitor canertinib on cell growth and survival in human melanoma cells in vitro and in vivo. Canertinib significantly inhibited growth of cultured melanoma cells, RaH3 and RaH5, in a dose-dependent manner as determined by cell counting. Half-maximum growth inhibitory dose (IC(50)) was approximately 0.8 μM and by 5 μM both cell lines were completely growth-arrested within 72 h of treatment. Incubation of exponentially growing RaH3 and RaH5 with 1 μM canertinib accumulated the cells in the G(1)-phase of the cell cycle within 24h of treatment without induction of apoptosis as determined by flow cytometry. Immunoblot analysis showed that 1 μM canertinib inhibited ErbB1-3 receptor phosphorylation with a concomitant decrease of Akt-, Erk1/2- and Stat3 activity in both cell lines. In contrast to the cytostatic effect observed at doses ≤ 5μM canertinib, higher concentrations induced apoptosis as demonstrated by the Annexin V method and Western blot analysis of PARP cleavage. Furthermore, canertinib significantly inhibited growth of RaH3 and RaH5 melanoma xenografts in nude mice. Pharmacological targeting of the ErbB receptors may prove successful in the treatment of patients with metastatic melanoma.[2]

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Intercellular communication between cellular compartments within the tumor and at distant sites is critical for the development and progression of cancer. Exosomes have emerged as potential regulators of intracellular communication in cancer. Exosomes are nanovesicles released by cells that contain biomolecules and are exchanged between cells. Exchange of exosomes between cells has been implicated in a number of processes critical for tumor progression and consequently altering exosome release is an attractive therapeutic target. Here, we review current understanding as well as gaps in knowledge regarding regulators of exosome release in cancer.[3]

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Surrogate animal models must be used for testing antiviral agents against variola (smallpox) virus infections. Once developed, these, compounds can be stockpiled for use in the event of a bioterrorist incident involving either variola or monkeypox virus, or used to treat an occasional serious orthopoxvirus infection, such as disseminated vaccinia complication following exposure to the live virus vaccine. Recently, considerable progress has been made in the discovery of novel antiviral agents found active against orthopoxviruses in vivo. This includes the development of new animal models or refinement of existing ones for compound efficacy testing. Current mouse models employ ectromelia, cowpox and vaccinia (WR and IHD strains) viruses with respiratory (lung) or tail lesion infections commonly studied. Rabbitpox and vaccinia (WR strain) viruses are available for rabbit infections. Monkeypox and variola viruses are used for infecting monkeys. This review describes these and other animal models, and covers compounds found active in vivo from 2003 to date. Cidofovir, known to be active against orthopox virus infections prior to 2003, has been studied extensively over recent years. New compounds showing promise are orally active inhibitors of orthopoxvirus infections that include ether lipid prodrugs of cidofovir and (S)-HPMPA, ST-246, N-methanocarbathymidine (N-MCT) and SRI 21950 (a 4'-thio derivative of iododeoxyuridine). Another compound with high activity but requiring parenteral administration is HPMPO-DAPy. Further development of these compounds is warranted.[4]

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Purpose: To determine the tolerability and pharmacokinetics of CI-1033 given daily for 7 days of a 21-day cycle. Tumor response and changes in erbB receptor tyrosine kinase activity in tumor and skin tissue were examined, and modulation of potential biomarkers in plasma was explored. Design: This was a dose-finding phase I study in patients with advanced solid malignancies. Patients were evaluated for safety, pharmacokinetics, and tumor response. Pharmacodynamic markers, such as Ki67, p27, and erbB receptor status, were assessed in tumor and skin tissue using immunohistochemical and immunoprecipitation methodologies. Plasma biomarkers HER2, vascular endothelial growth factor, interleukin-8, and matrix metalloproteinase-9 were evaluated using immunologic techniques. Results: Fifty-three patients were enrolled in the study. Dose-limiting toxicity (emesis, persistent rash, and mouth ulcer) was observed at 750 mg. The maximum tolerated dose was 650 mg. There were no confirmed objective responses. CI-1033 treatment showed down-regulation of epidermal growth factor receptor, HER2, and Ki67 in a variety of tumor tissues and up regulation of p27 in skin tissue. Plasma HER2 was reduced following CI-1033 administration, but no consistent change in vascular endothelial growth factor, interleukin-8, or matrix metalloproteinase-9 was noted. CI-1033 plasma concentrations were proportional to dose. Conclusion: The safety and pharmacokinetic profile of CI-1033 was favorable for multidose oral administration. Evidence of modulation of erbB receptor activity in tumor and skin tissue was accompanied by changes in markers of proliferation and cell cycle inhibition. Additional clinical trials are warranted in defining the role of CI-1033 in the treatment of cancer and further assessing the utility 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.)