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LDK378: A Promising Anaplastic Lymphoma Kinase (ALK) Inhibitor Jianyong Chen,* Cheng Jiang, and Shaomeng Wang Department of Internal Medicine, University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan 48109, United States
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on the phenyl ring by blocking the formation of reactive metabolites. These modifications ultimately yielded compound LDK378 (compound 6). In the GSH-trapping assay, 6 was found to have an almost undetectable level of GSH adduct (100 nM against all other kinases tested. Compound 6 showed potent antiproliferative activity with an IC50 value of 22.8 nM in Karpas 299 human non-Hodgkin’s Ki-positive large cell lymphoma carrying the NPM-ALK fusion gene and 26.0 nM in Ba/F3 cells transfected with the NPM-ALK fusion gene. Compound 6 also showed good selectivity over wild-type Ba/ F3 cells (IC50 > 2 μM) and Ba/F3 cells transfected with TelInsR gene (IC50 = 320 nM). Compound 6 has an excellent pharmacokinetics profile in rodents and non-rodents with an oral bioavailability of >50%. Compound 6 demonstrated dosedependent tumor growth inhibition and achieved partial tumor regression in the Karpas 299 rat xenograft model with daily administration but was capable of achieving complete tumor regression in the H2228 NSCLC rat xenograft model, which carries the EML4-ALK fusion gene. In both models, compound 6 was well tolerated in animals. Compound 6 was further assessed for its ADME profile and was found to have a relatively good metabolic stability in liver microsomes, modest CYP3A4 inhibition, some hERG inhibition with an IC50 value of 46 μM in hERG patch clamp experiments, but no evidence of QTc prolongation in both dog and monkey telemetry studies. Compound 6 is currently in phase 1/2 clinical trials for the treatment of patients with ALK-positive tumors. ALK is one of the highly competitive drug targets in oncology drug development. Although crizotinib was very effective for the treatment of ALK-positive NSCLC, acquired drug resistance caused by mutations of ALK has been identified in patients treated with crizotinib. Second-generation ALK inhibitors are now required to demonstrate efficacy against ALK mutants. In a phase 1 study with 88 patients with ALKpositive NSCLC, an overall response rate of 80% was observed in those treated with LDK378 who had experienced disease progression after initial treatment with crizotinib.8 In March 2013, LDK378 received the “breakthrough therapy” designation from the U.S. Food and Drug Administration (FDA) for
naplastic lymphoma kinase (ALK) is a receptor tyrosine kinase (RTK) belonging to the insulin receptor superfamily. ALK fusion genes have been identified in anaplastic large cell lymphomas (ALCL),1 inflammatory myofibroblastic tumor (IMT),2 diffuse large B-cell lymphoma (DLBCL),3 squamous cell carcinoma (SCC),4 and non-small-cell lung cancer (NSCLC).5 Among ALK fusion genes identified to date, nucleophosmin (NPM) is the most common partner in ALCL whereas echinoderm microtubule-associated protein-like-4 (EML4) is the main partner in NSCLC. The landmark discovery that the ALK fusion genes are oncogenic drivers in a small percentage of both blood cancers and solid tumors has generated intense interest for the development of potent and specific ALK inhibitors for the treatment of humans harboring a rearrangement of the ALK gene (ALK-positive tumors). A number of ALK inhibitors are currently in clinical development (Figure 1). Compound 1 (crizotinib) was initially designed as an inhibitor of c-Met kinase but was found to also possess a potent inhibitory activity of ALK. Seizing on this opportunity, Pfizer rapidly developed crizotinib as a new, molecularly targeted anticancer drug for the treatment of ALK-positive NSCLC patients and gained regulatory approval for marketing in 2011. In a phase 1 clinical trial conducted by Pfizer, crizotinib demonstrated an objective response rate of 57% in patients with ALK-positive NSCLC, which was unprecedented in lung cancer. It is truly remarkable that it only took 4 years from the discovery of ALK fusion genes (2007) to the market approval of the first ALK inhibitor for the treatment of ALK-positive NSCLC (2011). A number of other potent and more specific ALK inhibitors, including compounds 2 (X-396), 3 (CH5424802), 4 (ASP3026), and 6 (LDK378), are currently in phase 1/2 clinical trials. In the study published in the current issue of Journal of Medicinal Chemistry, Marsilje et al. from Novartis6 reported further optimization of a class of potent and specific ALK inhibitors, started from their previous clinical lead compound TAE684 (compound 5).7 Compound 5 was a potent and specific ALK inhibitor but was not suitable for clinical development. Compound 5 was found to generate a number of reactive adducts upon metabolic oxidation, which may create the potential for toxicological liabilities. The reactive metabolite formation in compound 5 was traced to the presence of a solubilizing group connected by a nitrogen atom onto the central aniline. This led to the design of analogues in which the piperidine at the para position of the aniline moiety in 5 was reversed. Additionally, replacement of the methoxy moiety in 5 by an isopropoxy moiety resulted in improved overall kinase selectivity and reduced metabolic liability associated with methoxy moiety. A methyl group at the position para to the isopropoxy moiety was used to further reduce the metabolism © XXXX American Chemical Society
Received: July 3, 2013
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dx.doi.org/10.1021/jm401005u | J. Med. Chem. XXXX, XXX, XXX−XXX
Journal of Medicinal Chemistry
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Figure 1. Chemical structures of representative ALK inhibitors. positive diffuse large B-cell lymphoma is associated with clathrin-ALK rearrangements: report of 6 cases. Blood 2003, 102, 2568−2573. (4) Jazii, F. R.; Najafi, Z.; Malekzadeh, R.; Conrads, T. P.; Ziaee, A. A.; Abnet, C.; Yazdznbod, M.; Karkhane, A. A.; Salekdeh, G. H. Identification of squamous cell carcinoma associated proteins by proteomics and loss of beta tropomyosin expression in esophageal cancer. World J. Gastroenterol. 2006, 12, 7104−7112. (5) Soda, M.; Choi, Y. L.; Enomoto, M.; Takada, S.; Yamashita, Y.; Ishikawa, S.; Fujiwara, S.; Watanabe, H.; Kurashina, K.; Hatanaka, H.; Bando, M.; Ohno, S.; Ishikawa, Y.; Aburatani, H.; Niki, T.; Sohara, Y.; Sugiyama, Y.; Mano, H. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature 2007, 448, 561−566. (6) Marsilje, T. H.; Pei, W.; Chen, B.; Lu, W.; Uno, T.; Jin, Y.; Jiang, T.; Kim, S.; Li, N.; Warmuth, M.; Sarkisova, Y.; Sun, F.; Steffy, A.; Pferdekamper, A. C.; Li, A. G.; Joseph, S. B.; Kim, Y.; Liu, B.; Tuntland, T.; Cui, X.; Gray, N. S.; Steensma, R.; Wan, Y.; Jiang, J.; Chopiuck, G.; Li, J.; Gordon, W. P.; Richmond, W.; Johnson, K.; Chang, J.; Groessl, T.; He, Y.-Q.; Phimister, A.; Aycinena, A.; Lee, C. C.; Bursulaya, B.; Karanewsky, D. S.; Seidel, H. M.; Harris, J. L.; Michellys, P.-Y. Synthesis, structure−activity relationships, and in vivo efficacy of the novel potent and selective anaplastic lymphoma kinase (ALK) inhibitor 5‑chloro‑N2‑(2-isopropoxy-5-methyl-4-(piperidin-4yl)phenyl)‑N4‑(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine (LDK378) currently in phase 1 and phase 2 clinical trials. J. Med. Chem. 2013, DOI: 10.1021/jm400402q. (7) Galkin, A. V.; Melnick, J. S.; Kim, S.; Hood, T. L.; Li, N.; Li, L.; Xia, G.; Steensma, R.; Chopiuk, G.; Jiang, J.; Wan, Y.; Ding, P.; Liu, Y.; Sun, F.; Schultz, P. G.; Gray, N. S.; Warmuth, M. Identification of NVP-TAE684, a potent, selective, and efficacious inhibitor of NPMALK. Proc. Natl. Acad. Sci. U.S.A. 2007, 104, 270−275. (8) Pharma Times, Novartis NSCLC drug classed as breakthrough in U.S., March 18, 2013.
treating patients with anaplastic lymphoma kinase positive (ALK+) metastatic non-small-cell lung cancer (NSCLC) who had progressed during treatment with, or were intolerant to, Pfizer’s crizotinib.8 The “breakthrough therapy” designation is intended to expedite the development and review of drugs that treat life-threatening conditions and show improvement over available therapies. It is expected that LDK378 and a number of other second-generation of ALK inhibitors now in clinical development will soon become powerful new medicines for the treatment of patients with ALK-positive tumors. The study by Marsilje et al.6 is an excellent example of rational drug optimization in which extensive medicinal chemistry efforts were undertaken to address critical defects uncovered for initial lead compounds. The optimized ALK inhibitor 6 (LDK378) that was revealed in that study has already demonstrated great promise for the treatment of patients with ALK-positive NSCLC.
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AUTHOR INFORMATION
Corresponding Author
*Phone: 734-6158495. Fax: 734-6479647. E-mail: jiachen@ umich.edu.
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REFERENCES
(1) Webb, T. R.; Slavish, J.; George, R. E.; Look, A. T.; Xue, L.; Jiang, Q.; Cui, X.; Rentrop, W. B.; Morris, S. W. Anaplastic lymphoma kinase: role in cancer pathogenesis and small-molecule inhibitor development for therapy. Expert Rev. Anticancer Ther. 2009, 9, 331− 356. (2) Griffin, C. A.; Hawkins, A. L.; Dvorak, C.; Henkle, C.; Ellingham, T.; Perlman, E. J. Recurrent involvement of 2p23 in inflammatory myofibroblastic tumors. Cancer Res. 1999, 59, 2776−2780. (3) Gascoyne, R. D.; Lamant, L.; Martin-Subero, J. I.; Lestou, V. S.; Harris, N. L.; Muller-Hermelink, H. K.; Seymour, J. F.; Campbell, L. J.; Horsman, D. E.; Auvigne, I.; Espinos, E.; Siebert, R.; Delsol, G. ALKB
dx.doi.org/10.1021/jm401005u | J. Med. Chem. XXXX, XXX, XXX−XXX
