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Chemical Compound Review

Canertinib HCl     N-[4-[(3-chloro-4-fluoro- phenyl)amino]-7...

Synonyms: CHEMBL31965, S1019_Selleck, CHEMBL545315, cc-446, SureCN2052123, ...
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Disease relevance of CI-1033

  • In an in vivo lethal vaccinia virus pneumonia model, CI-1033 alone promotes survival of animals, augments systemic T cell immunity and, in conjunction with a single dose of anti-L1R intracellular mature virus particle-specific mAb, fosters virtually complete viral clearance of the lungs of infected mice by the eighth day after infection [1].
  • Infection of monkey kidney BSC-40 and VERO-E6 cells in vitro by variola strain Solaimen is blocked by CI-1033, primarily at the level of secondary viral spreading [1].
  • Multicenter, randomized phase II trial of oral CI-1033 for previously treated advanced ovarian cancer [2].
  • Colony-forming assays revealed that the antiproliferative effects of simultaneous treatment with CI1033 and SN-38 were synergistic in T98G glioblastoma cells and HCT8 colorectal carcinoma cells, whereas sequential treatments were additive at best [3].
  • PURPOSE: In phase I studies with oral CI-1033, dose-limiting toxicities were primarily gastrointestinal, supporting the exploration of i.v. dosing to achieve optimal drug exposures by increasing bioavailability [4].

High impact information on CI-1033

  • Here we show that CI-1033 and related 4-anilinoquinazolines inhibit SPGF-induced human cellular DNA synthesis, protein tyrosine kinase activation, and c-Cbl association with ErbB-1 and resultant internalization [1].
  • PATIENTS AND METHODS: This phase II, open-label clinical trial evaluated CI-1033 in patients with ovarian cancer who failed prior platinum-based therapy [2].
  • PURPOSE: To evaluate the antitumor activity and toxicity of two doses of CI-1033 in patients with platinum-refractory or recurrent ovarian cancer, and to determine baseline expression of epidermal growth factor receptor in tumor cells [2].
  • The HER tyrosine kinase inhibitor CI1033 enhances cytotoxicity of 7-ethyl-10-hydroxycamptothecin and topotecan by inhibiting breast cancer resistance protein-mediated drug efflux [3].
  • Conversely, CI1033 accumulation was diminished in cells expressing BCRP, suggesting that CI1033 is a substrate for this efflux pump [3].

Chemical compound and disease context of CI-1033


Biological context of CI-1033

  • Furthermore, tumors that depend on ErbB receptor signaling for survival and exhibit activated p38 in the basal state may be susceptible to apoptosis by CI-1033 as a single agent [7].
  • Treatment of BT474 cells with CI-1033 inhibited both the phosphorylation of Akt and MAPK and resulted in a 47% apoptotic fraction [7].
  • Treatment with the pan-ErbB inhibitor CI1033 and the anti-EGF receptor (EGFR) antibody C225 demonstrated that ligand-mediated activation of EGFR is required for SUM149 cell proliferation [8].
  • Phase 1 clinical and pharmacokinetics evaluation of oral CI-1033 in patients with refractory cancer [9].
  • At equivalent doses, the bioavailability of i.v. CI-1033 is thrice that of the oral formulation [4].

Anatomical context of CI-1033


Associations of CI-1033 with other chemical compounds

  • Expression of the glucose transporter Glut-1 and cell cycle markers was unchanged or increased in control tumours and generally decreased with CI-1033 treatment, compared to baseline [6].
  • In this review, results of most recent clinical with EGFR inhibitors including monoclonal antibodies, such as Trastuzumab (Herceptin), IMC-C225 (Cetuximab) and others (ABX-EGF, EMD 72000), and tyrosine-kinase inhibitors, such as ZD1839 (Gefitinib, Iressa), OSI-774 (Erlotinib, Tarceva) and others (CI-1033, GW2016), are summarized [11].

Gene context of CI-1033

  • In the present studies, mice bearing established xenografts (A431 epidermoid carcinoma, H125 non-small cell lung carcinoma, SF767 glioblastoma, and MDA-MB-468 mammary carcinoma) were treated with efficacious and subefficacious doses of CI-1033, and plasma levels and xenograft gene expression of VEGF and IL-8 were evaluated [12].
  • In contrast, subefficacious doses of CI-1033 did not significantly affect VEGF or IL-8 levels in any of the xenograft models [12].
  • Moreover, CI1033 enhanced the uptake and cytotoxicity of SN-38 and TPT in cells transfected with BCRP but not empty vector [3].
  • METHODS: Mice bearing subcutaneous A431 human squamous carcinoma xenografts (n=6-8) were treated with the pan-Erb-B inhibitor CI-1033 or vehicle and imaged serially (days 0, 3 and 6 or 7) with [(18)F]fluorodeoxyglucose, [(18)F]fluoro-L: -thymidine, [(18)F]fluoro-azoazomycinarabinoside or [(18)F]fluoromisonidazole [6].
  • Thymidine kinase activity was reduced in all tumours compared to baseline at day 3 but was sevenfold higher in control versus CI-1033-treated tumours by day 6 of treatment [6].

Analytical, diagnostic and therapeutic context of CI-1033

  • Analysis of intracellular SN-38 levels by high-performance liquid chromatography and intracellular TPT levels by flow microfluorometry revealed that CI1033 increased the steady-state accumulation of SN-38 and TPT by 9.4 +/- 1.9- and 1.8 +/- 0.2-fold, respectively [3].
  • In additional studies examining the mechanistic basis for these findings in T98G cells, immunoblotting revealed that the inhibitory effects of CI1033 on epidermal growth factor receptor autophosphorylation were unaffected by SN-38 [3].
  • Two compounds were evaluated against A431, H125, and MCF-7 xenografts in nude mice but were inferior in these assays to the clinical trial compound CI-1033 [13].
  • Thus, CI-1033, which is currently undergoing phase I clinical trials, holds significant potential for use in a broad range of solid tumors [14].
  • In order to define proteins involved in the regulation of apoptosis, we aimed to determine differences in the proteome profile of both cell lines before and after treatment with CI-1033 [15].


  1. Antiviral chemotherapy facilitates control of poxvirus infections through inhibition of cellular signal transduction. Yang, H., Kim, S.K., Kim, M., Reche, P.A., Morehead, T.J., Damon, I.K., Welsh, R.M., Reinherz, E.L. J. Clin. Invest. (2005) [Pubmed]
  2. Multicenter, randomized phase II trial of oral CI-1033 for previously treated advanced ovarian cancer. Campos, S., Hamid, O., Seiden, M.V., Oza, A., Plante, M., Potkul, R.K., Lenehan, P.F., Kaldjian, E.P., Varterasian, M.L., Jordan, C., Charbonneau, C., Hirte, H. J. Clin. Oncol. (2005) [Pubmed]
  3. The HER tyrosine kinase inhibitor CI1033 enhances cytotoxicity of 7-ethyl-10-hydroxycamptothecin and topotecan by inhibiting breast cancer resistance protein-mediated drug efflux. Erlichman, C., Boerner, S.A., Hallgren, C.G., Spieker, R., Wang, X.Y., James, C.D., Scheffer, G.L., Maliepaard, M., Ross, D.D., Bible, K.C., Kaufmann, S.H. Cancer Res. (2001) [Pubmed]
  4. Increased bioavailability of intravenous versus oral CI-1033, a pan erbB tyrosine kinase inhibitor: results of a phase I pharmacokinetic study. Simon, G.R., Garrett, C.R., Olson, S.C., Langevin, M., Eiseman, I.A., Mahany, J.J., Williams, C.C., Lush, R., Daud, A., Munster, P., Chiappori, A., Fishman, M., Bepler, G., Lenehan, P.F., Sullivan, D.M. Clin. Cancer Res. (2006) [Pubmed]
  5. Radiosensitization of human breast cancer cells by a novel ErbB family receptor tyrosine kinase inhibitor. Rao, G.S., Murray, S., Ethier, S.P. Int. J. Radiat. Oncol. Biol. Phys. (2000) [Pubmed]
  6. Multi-tracer small animal PET imaging of the tumour response to the novel pan-Erb-B inhibitor CI-1033. Dorow, D.S., Cullinane, C., Conus, N., Roselt, P., Binns, D., McCarthy, T.J., McArthur, G.A., Hicks, R.J. Eur. J. Nucl. Med. Mol. Imaging (2006) [Pubmed]
  7. Akt, MAPK (Erk1/2), and p38 act in concert to promote apoptosis in response to ErbB receptor family inhibition. Nelson, J.M., Fry, D.W. J. Biol. Chem. (2001) [Pubmed]
  8. Autocrine and juxtacrine effects of amphiregulin on the proliferative, invasive, and migratory properties of normal and neoplastic human mammary epithelial cells. Willmarth, N.E., Ethier, S.P. J. Biol. Chem. (2006) [Pubmed]
  9. Phase 1 clinical and pharmacokinetics evaluation of oral CI-1033 in patients with refractory cancer. Nemunaitis, J., Eiseman, I., Cunningham, C., Senzer, N., Williams, A., Lenehan, P.F., Olson, S.C., Bycott, P., Schlicht, M., Zentgraff, R., Shin, D.M., Zinner, R.G. Clin. Cancer Res. (2005) [Pubmed]
  10. Radiosensitization by pan ErbB inhibitor CI-1033 in vitro and in vivo. Nyati, M.K., Maheshwari, D., Hanasoge, S., Sreekumar, A., Rynkiewicz, S.D., Chinnaiyan, A.M., Leopold, W.R., Ethier, S.P., Lawrence, T.S. Clin. Cancer Res. (2004) [Pubmed]
  11. Epidermal growth factor receptor inhibitors: a new prospective in the treatment of lung cancer. Tiseo, M., Loprevite, M., Ardizzoni, A. Current medicinal chemistry. Anti-cancer agents. (2004) [Pubmed]
  12. Plasma vascular endothelial growth factor and interleukin-8 as biomarkers of antitumor efficacy of a prototypical erbB family tyrosine kinase inhibitor. Christensen, J.G., Vincent, P.W., Klohs, W.D., Fry, D.W., Leopold, W.R., Elliott, W.L. Mol. Cancer Ther. (2005) [Pubmed]
  13. Tyrosine kinase inhibitors. 18. 6-Substituted 4-anilinoquinazolines and 4-anilinopyrido[3,4-d]pyrimidines as soluble, irreversible inhibitors of the epidermal growth factor receptor. Smaill, J.B., Showalter, H.D., Zhou, H., Bridges, A.J., McNamara, D.J., Fry, D.W., Nelson, J.M., Sherwood, V., Vincent, P.W., Roberts, B.J., Elliott, W.L., Denny, W.A. J. Med. Chem. (2001) [Pubmed]
  14. CI-1033, a pan-erbB tyrosine kinase inhibitor. Slichenmyer, W.J., Elliott, W.L., Fry, D.W. Semin. Oncol. (2001) [Pubmed]
  15. Irreversible pan-ErbB tyrosine kinase inhibitor CI-1033 induces caspase-independent apoptosis in colorectal cancer DiFi cell line. Skvortsov, S., Skvortsova, I., Sarg, B., Loeffler-Ragg, J., Lindner, H., Lukas, P., Tabernero, J., Zwierzina, H. Apoptosis (2005) [Pubmed]
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