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{{Chembox | verifiedrevid = 434316721 | ImageFile = Crenolanib.svg | ImageSize = 200px | IUPACName = 1-(2-{5--1H-benzimidazol-1-yl}quinolin-8-yl)piperidin-4-amine | OtherNames = CP-868,596; ARO 002 | Section1 = ! colspan=2 style="background: #f8eaba; text-align: center;" |Identifiers

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• InChI=1S/C26H29N5O2/c1-26(14-32-15-26)16-33-20-6-7-22-21(13-20)28-17-31(22)24-8-5-18-3-2-4-23(25(18)29-24)30-11-9-19(27)10-12-30/h2-8,13,17,19H,9-12,14-16,27H2,1H3Key: DYNHJHQFHQTFTP-UHFFFAOYSA-N

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Crenolanib is an investigational new drug being developed by AROG Pharmaceuticals, LLC for the treatment of certain types of cancer. Crenolanib is a tyrosine kinase inhibitor that acts by specifically inhibiting the receptor tyrosine kinases PDGFRA and PDGFRB.

Contents

Crenolanib is an orally bioavailable, selective small molecule inhibitor of the Platelet-derived growth factor receptor PDGFR) tyrosine kinase, inhibiting both PDGFRA and PDGFRB at picomolar concentrations.

Type III receptor tyrosine kinases (RTK), including c-KIT, PDGFRα and PDGFRβ, have been directly implicated in the pathogenesis of epithelial, mesenchymal, and hematological malignancies. The PDGF/PDGFR pathway is the primary driver of oncogenesis in several malignancies including gastrointestinal stromal tumor (GIST), both adult and pediatric gliomas, as well as a subset of Non-small-cell lung carcinoma (NSCLC). These malignancies often respond to treatment with non-selective inhibitors of PDGFR like imatinib and sunitinib. Crenolanib is a 100-500-fold more potent inhibitor of PDGFRα and PDGFRβ than other commercially available TKIs. It is currently being developed as an antineoplastic agent in cancers.

Clinical

Phase I single-agent and Phase Ib combination studies have investigated the clinical pharmacology of crenolanib in patients with cancer. Pharmacokinetic and safety studies of CP-868,596 administered alone or in combination with docetaxel with or without axitinib have been completed. Results suggest that CP-868,596 is well tolerated as a single agent, and can also be safely combined with docetaxel and axitinib due to their non-overlapping toxicity profiles.

Proposed clinical trials

AROG Pharmaceuticals is planning three clinical trials for crenolanib:

• A Phase II Study of crenolanib in patients with adult gliomas
• A Phase II Study of crenolanib in patients with advanced gastrointestinal stromal tumors (GIST) with the D842V mutation in the PDGFRA gene
• A Phase I/II clinical trial evaluating crenolanib as a single agent in children with recurrent, progressive or refractory high-grade glioma, as well as in combination with radiation for the treatment of children with newly diagnosed high grade glioma (HGG), including diffuse intrinsic pontine glioma.

References

1. Lemmon, Mark A.; Schlessinger, Joseph (2010). "Cell Signaling by Receptor Tyrosine Kinases". Cell. 141 (7): 1117–1134. doi:10.1016/j.cell.2010.06.011. PMC 2914105. PMID 20602996.
2. Heinrich, M. C.; Corless, CL; Demetri, GD; Blanke, CD; Von Mehren, M; Joensuu, H; McGreevey, LS; Chen, CJ; Van Den Abbeele, AD (2003). "Kinase Mutations and Imatinib Response in Patients with Metastatic Gastrointestinal Stromal Tumor". Journal of Clinical Oncology. 21 (23): 4342–4349. doi:10.1200/JCO.2003.04.190. PMID 14645423.
3. Verhaak, Roel G.W.; Hoadley, Katherine A.; Purdom, Elizabeth; Wang, Victoria; Qi, Yuan; Wilkerson, Matthew D.; Miller, C. Ryan; Ding, Li; Golub, Todd (2010). "Integrated Genomic Analysis Identifies Clinically Relevant Subtypes of Glioblastoma Characterized by Abnormalities in PDGFRA, IDH1, EGFR, and NF1". Cancer Cell. 17 (1): 98–110. doi:10.1016/j.ccr.2009.12.020. PMC 2818769. PMID 20129251.
4. Paugh, B. S.; Qu, C.; Jones, C.; Liu, Z.; Adamowicz-Brice, M.; Zhang, J.; Bax, D. A.; Coyle, B.; Barrow, J. (2010). "Integrated Molecular Genetic Profiling of Pediatric High-Grade Gliomas Reveals Key Differences with the Adult Disease". Journal of Clinical Oncology. 28 (18): 3061–3068. doi:10.1200/JCO.2009.26.7252. PMC 2903336. PMID 20479398.
5. Ramos, Alex H.; Dutt, Amit; Mermel, Craig; Perner, Sven; Cho, Jeonghee; Lafargue, Christopher J.; Johnson, Laura A.; Stiedl, Ann-Cathrin; Tanaka, Kumiko E. (2009). "Amplification of chromosomal segment 4q12 in non-small cell lung cancer". Cancer Biology & Therapy. 8 (21): 2042–2050. doi:10.4161/cbt.8.21.9764. PMC 2833355. PMID 19755855.
6. Lewis, N. L.; Lewis, L. D.; Eder, J. P.; Reddy, N. J.; Guo, F.; Pierce, K. J.; Olszanski, A. J.; Cohen, R. B. (2009). "Phase I Study of the Safety, Tolerability, and Pharmacokinetics of Oral CP-868,596, a Highly Specific Platelet-Derived Growth Factor Receptor Tyrosine Kinase Inhibitor in Patients with Advanced Cancers". Journal of Clinical Oncology. 27 (31): 5262–5269. doi:10.1200/JCO.2009.21.8487. PMC 2773478. PMID 19738123.
7. Michael, M; Vlahovic, G; Khamly, K; Pierce, K J; Guo, F; Olszanski, A J (2010). "Phase Ib study of CP-868,596, a PDGFR inhibitor, combined with docetaxel with or without axitinib, a VEGFR inhibitor". British Journal of Cancer. 103 (10): 1554–1561. doi:10.1038/sj.bjc.6605941. PMC 2990584. PMID 20959830.
8. NCT01229644: A Study of CP-868,596, a Selective and Potent Inhibitor of Platelet-Derived Growth Factor Receptors (PDGFR), for the Treatment of Adult Gliomas
9. NCT01243346: Evaluation of CP-868,596 in Patients With Advanced Gastrointestinal Stromal Tumour (GIST) With the D842V Mutation in the PDGFRA Gene

External links

• "PDGFR Inhibitor CP-868596 (Code C64639)", National Cancer Institute Thesaurus.
• "PDGFR and Human Cancer" , AROG Pharmaceuticals LLC.

• Tyrosine kinase inhibitors
• Oxetanes
• Quinolines
• Piperidines
• Benzimidazoles