Crenolanib

Crenolanib
IUPAC name 1-(2-{5-[(3-Methyloxetan-3-yl)methoxy]-1H-benzimidazol-1-yl}quinolin-8-yl)piperidin-4-amine
Other names CP-868,596; ARO 002
Identifiers
CAS number	670220-88-9
PubChem	10366136
ChemSpider	8541584 Y
Jmol-3D images	Image 1
SMILES O(c5cc4ncn(c1nc3c(cc1)cccc3N2CCC(N)CC2)c4cc5)CC6(COC6)C
InChI 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,9-12,14-16,27H2,1H3 Y Key: DYNHJHQFHQTFTP-UHFFFAOYSA-N Y
Properties
Molecular formula	C26H29N5O2
Molar mass	443.54 g mol−1
Y (verify) (what is: Y/N?) Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa)
Infobox references

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.^[1] The PDGF/PDGFR pathway is the primary driver of oncogenesis in several malignancies including gastrointestinal stromal tumor (GIST),^[2] both adult^[3] and pediatric gliomas,^[4] as well as a subset of Non-small-cell lung carcinoma (NSCLC).^[5] 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^[6] and Phase Ib combination^[7] 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^[8]
• A Phase II Study of crenolanib in patients with advanced gastrointestinal stromal tumors (GIST) with the D842V mutation in the PDGFRA gene^[9]
• 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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2914105. 
2. ^ Heinrich, M. C.; Corless, CL; Demetri, GD; Blanke, CD; Von Mehren, M; Joensuu, H; McGreevey, LS; Chen, CJ et al. (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 et al. (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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2818769. 
4. ^ Paugh, B. S.; Qu, C.; Jones, C.; Liu, Z.; Adamowicz-Brice, M.; Zhang, J.; Bax, D. A.; Coyle, B. et al. (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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2903336. 
5. ^ Ramos, Alex H.; Dutt, Amit; Mermel, Craig; Perner, Sven; Cho, Jeonghee; Lafargue, Christopher J.; Johnson, Laura A.; Stiedl, Ann-Cathrin et al. (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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2833355. 
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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2773478. 
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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2990584. 
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.