Abstract
The anaplastic lymphoma kinase (ALK) receptor tyrosine kinase represents a potential therapeutic target. Specially, a variety of alterations in the ALK gene including mutations, overexpression, amplification, translocations and structural rearrangements, are involved in human cancer tumorigenesis. The second-generation ALK inhibitor CH5424802 (development code: AF802; Chugai Pharmaceutical, a subsidiary of Roche) achieves tumor regression with excellent tolerance and shows promising efficacy in patients with ALK-positive non-small cell lung cancer. CH5424802 shows good kinase selectivity, has a promising pharmacokinetics profile, and has strong antiproliferative activity in several ALK-driven tumor models. CH5424802 has also shown anti-tumor activity in mouse xenograft studies. Here, we summarize recent advances and the evidence that CH5424802 acts as an ALK inhibitor. We also discuss its potential for further development as an anticancer drug in clinical trials.
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Lung cancer is often fatal and has a higher mortality rate than breast, colorectal and prostate cancer (Pirozynski 2006; Siegel et al. 2013). Clinically, lung cancers can be classified as small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), with SCLC and NSCLC accounting for 80–85 % of all lung cancers. Despite committed efforts to improve lung cancer diagnosis and treatment, the 5-year survival rate for patients with NSCLC remains low at ~10–15 %. More than 50 % of patients are diagnosed at advanced stages of the disease; at that point, treatment has a palliative rather than a curative intent (Scagliotti 2007; McDermott et al. 2008).
A new era for cancer therapy has dawned in recent years with the development of novel methods for identifying and targeting tumors’ molecular defects. Targeted therapies appear promising and offer new therapeutic models in the field of oncology. While numerous kinase inhibitors have been developed to treat a broad range of cancers, 208 NSCLC-targeting drugs are now in development: 17 in phase III, 130 in phase II, and 61 in phase I (White 2012). Targeted therapies dominate all stages of the NSCLC pipeline, and the major strategy of the late-phase drugs is inhibition of tyrosine kinases such as anaplastic lymphoma kinase (ALK).
Anaplastic lymphoma kinase belongs to the family of tyrosine kinase receptors (TKRs). Recently, ALK-TKR has emerged as a potential biomarker and therapeutic target in solid and hematologic tumors (Cabezón-Gutiérrez et al. 2012; La Madrid et al. 2012). In the ALK gene, a variety of genetic alterations such as mutations, overexpression, amplification, translocations, or other structural rearrangements, have been implicated in anaplastic large cell lymphoma (ALCL) and in a subset of NSCLC, suggesting ALK addiction in human cancer (Azarova et al. 2011; Soda et al. 2007; Shigematsu et al. 2005; Webb et al. 2009).
ALK tyrosine kinase activity is necessary for its transforming activity and oncogenicity (Sasaki et al. 2010; Koivunen et al. 2008). Crizotinib (PF-02341066, Xalkori) as the first-generation of ALK inhibitor was developed by Pfizer and approved as a dual MET/ALK inhibitor for treating NSCLC with ALK translocations in August of 2011. Crozotinib-mediated inactivation of EML4–ALK kinase caused the disengagement of oncogenic signaling pathways and induced growth arrest and cell death, but made tumors acquire resistance. Therefore, numerous ALK kinase inhibitors (Table 1) have been in clinical evaluation as potential therapies as second-generation ALK inhibitors (Soda et al. 2008; McDermott et al. 2008). This report highlights the clinical, biological, and molecular features of CH5424802 and discusses the use of CH5424802 as a ‘druggable’ ALK inhibitor for cancer therapy.
CH5424802 as an orally active, potent, and highly selective ALK inhibitor, is currently advancing in human clinical trials (Kinoshita et al. 2011a, 2011b, 2012). As an ATP-competitive inhibitor, CH5424802 exhibits strong antiproliferative activity in NSCLC and ALCL. Molecular modeling analysis revealed its binding to the ATP site of ALK in the DFG-in mode (Sakamoto et al. 2011; Kinoshita et al. 2011b). In an enzymatic activity assay, CH5424802 inhibits ALK activity at nanomolar concentrations (IC50, 1.9 nM; Kd, 2.4 nM; Ki, 0.83 nM) and exhibits good kinase selectivity; among 402 kinases, only three kinases, ALK, cyclin G-associated kinase (GAK), and leukocyte tyrosine kinase (LTK) showed greater than 50 % inhibition at 10 nM CH5424802 (Sakamoto et al. 2011). The inhibitory action of CH5424802 can be explained by the high sequence similarity of LTK to ALK (Iwahara et al. 1997). In NSCLC expressing echinoderm microtubule-associated protein-like 4 (EML4)-ALK fusion oncogene (Soda et al. 2007), CH5424802 exhibited preferential antitumor activity. CH5424802 also exhibited antitumor activity in ALCL expressing the nucleophosmin (NPM)-ALK fusion. About 50–60 % of ALCLs possesses a reciprocal chromosomal translocation that fuses NPM to ALK, thus forming a soluble chimeric and oncogenic NPM-ALK (Bischof et al. 1997).
The good pharmacokinetic profile of CH5424802 has been linked with its strong antiproliferative activity in ALK-driven tumor models (Sakamoto et al. 2011). The half-life and the oral bioavailability of CH5424802 in mice were 8.6 h and 70.8 %, respectively. No differences in body weight or gross signs of toxicity were observed in CH5424802-treated mice at any dose level. In the mouse xenograft model inoculating NCI-H2228 cells (a NSCLC-expressing EML4-ALK), the oral administration of CH5424802 dose-dependently inhibited tumor growth with an ED50 of 0.46 mg/kg, but not in the xenograft model inoculating A549 cells that is an NSCLC cell line that does not express ALK fusions.
In the mode of action study, CH5424802 prevents ALK autophosphorylation in NCI-H2228 cells (Sakamoto et al. 2011). CH5424802 also suppresses the phosphorylation of STAT3 and AKT in NCI-H2228. The inhibitory effect of CH5424802 on the phosphorylation of ALK and STAT3 was confirmed in in vivo models. In the ALK-positive ALCL cell line KARPAS-299, CH5424802 completely inhibited the phosphorylation of STAT3 (Sakamoto et al. 2011). STAT3 is required for ALK-mediated lymphomagenesis in ALCL (Chiarle et al. 2005).
Furthermore, CH5424802 exhibited anticancer potency against the L1196 M gatekeeper mutation of ALK accompanied with the inhibition of both ALK and STAT3 phosphorylation (Sakamoto et al. 2011). L1196 M, in which methionine is substituted for leucine at position 1,196 in ALK, exhibited increased kinase activity compared with wild-type ALK (Lu et al. 2009).
The results for the first-in-human phase I/II study of CH5424802 in patients with ALK-positive NSCLC has been reported recently (Kiura 2012). The highest dose level defined in the protocol, 300 mg b.i.d., did not reach the maximum tolerated dose, and toxicities were mild to moderate. Importantly, all patients achieved tumor regression at all dose levels, suggesting that it could be well tolerated. The promising efficacy of CH5424802 in patients with ALK-positive NSCLC hints at further success in the ongoing phase II and advanced trials. Hopefully, the effort to develop potent ALK inhibitors such as CH5424802 will result in clinical process in cancer treatment for patients with ALK-driven tumors.
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This work was supported by KRICT’s project, SI-1304, funded by the Ministry of Knowledge Economy, Republic of Korea.
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Latif, M., Saeed, A. & Kim, S.H. Journey of the ALK-inhibitor CH5424802 to phase II clinical trial. Arch. Pharm. Res. 36, 1051–1054 (2013). https://doi.org/10.1007/s12272-013-0157-8
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DOI: https://doi.org/10.1007/s12272-013-0157-8