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Novel Anaplastic Lymphoma Kinase Inhibitors Targeting Clinically Acquired Resistance Xiaoyun Lu and Ke Ding* Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, #190 Kaiyuan Avenue, Guangzhou, 510530, China ABSTRACT: The study by Huang et al. is an excellent example of rational structure-based and lipophilic-efficiency optimization of crizotinib (Xalkori) aimed at novel ALK inhibitors capable of overcoming clinically acquired resistance against the current drug in NSCLC patients. One of the most promising new compounds, 8e, displayed subnanomolar potency against ALKWT and a panel of the crizotinib-resistant mutants and demonstrated robust in vivo antitumor efficacy. The super suppressing potency of this compound on ROS1 kinase may also indicate its great potential to overcome the resistance associated with the most recently identified ROS1 mutation.
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naplastic lymphoma kinase (ALK) is a tyrosine kinase belonging to the insulin receptor superfamily. The constitutively active ALK fusion genes have been oncogenically linked with multiple types of human cancer, including anaplastic large cell lymphoma (ALCL), inflammatory myofibroblastic tumor (IMT), diffuse large B-cell lymphoma (DLBCL), and non-small cell lung cancer (NSCLC), among others. For instance, the echinoderm microtubule-associated protein-like-4 (EML4)-ALK fusion gene has been proved to be the driving force in approximately 5% of NSCLC patients, making it an attractive molecular target for oncology drug development.1 The first generation ALK inhibitor crizotinib (1, Xalkori), from Pfizer, was approved in 2011 as the first-line drug for the management of ALK-positive (or ALK-rearranged) NSCLC patients. Clinical investigations on the potential application of this drug to ALCL and other advanced solid tumors are also continuing.2 Despite the remarkable clinical benefit achieved by crizotinib, which has objective response rates of 60% and progression-free survival of approximately 10 months, clinically acquired resistance remains a serious clinical challenge. A number of new generation ALK inhibitors (Figure 1) that overcome resistance to crizotinib are currently in different stages of development.2 Comparable to the mutation of EGFR to gefitinib, the secondary mutation of EML4-ALK is a well characterized mechanism underlying acquired resistance against crizotinib. In this case, the leucine1196 → methionine1196 (L1196M) “gate-keeper” mutation is most frequently detected.3 In the study published in this issue of J. Med. Chem., Huang and colleagues from Pfizer report the rational design starting from structural feature analysis of the crizotinib−ALK complex, of 3-benzyloxy aminopyridine derivatives, new ALK inhibitors capable of inhibiting the crizotinib-resistant mutants including L1196M.4 High resolution X-ray crystal structures revealed that crizotinib binds similarly with the wild type ALK (ALKWT) and with the L1196M mutant. Comparison of the apo structure of ALK to the crizotinib−ALK complex, however, suggests that the 2-chloro substituent in crizotinib forces an unfavorable rotation of the backbone carbonyl of glycine1269 (G1269, in ALK). In light of this observation, the 2-des-chloro analogue (1a) was first designed to relax the G1269 carbonyl and © 2014 American Chemical Society
Figure 1. Second generation ALK inhibitors with the capability of inhibiting the crizotinib-resistant mutants.
improve the potency. Indeed, 1a exhibits increased ALK inhibitory potency, with IC50 values of 5.0 and 387 nM against ALKL1196M kinase and the cells stably expressing L1196M mutant. Subsequent structural optimization of 1a led to the discovery of the triazole analogue 6d (Figure 2), which displays significantly improved ALKL1196M inhibitory potency, cell growth inhibition, lipophilic efficiency (LipE), and absorption, distribution, metabolism, and excretion (ADME) properties. The cocrystal structure of 6d complexed with ALK was also solved to demonstrate that the triazole group of 6d makes contact with the ALK G-loop residues by forming a 60° torsion angle with the phenyl ring in 6d, which may contribute greatly to the improvement in potency. Although 6d exhibited good potency and a reasonable in vitro ADME profile, the unsubstituted pyrazole tail makes the Received: February 2, 2014 Published: February 5, 2014 1167
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Figure 2. Structure-based and lipophilic-efficiency focused optimization of crizotinib to yield a new generation ALK inhibitors.
Food and Drug Administration (FDA).2 An approximately 93.5% objective response rate was observed in a phase I/II clinical trial of CH5424802 to treat crizotinib-naive and relapsed ALK-positive NSCLC patients.5 Another compound, AP26113, has also been demonstrated to show a high response rate in ALK positive NSCLC patients with pre-existing brain metastases.6 However, a recent report revealed that a point mutation in ROS1 kinase also confers resistance against crizotinib in NSCLC patients.7 Given its superinhibitory potency against ROS1 with an IC50 value of 20 pM, it is enthusiastically predicted that compound 8e will also display great potential to overcome the ROS1 mutation associated resistance. Overall, the study by Huang et al.4 provides an excellent example of rational structure-based and lipophilic-efficiency optimization of a clinical drug to overcome the clinically acquired resistance. These efforts eventually led to the discovery of the novel ALK inhibitor 8e as a highly promising clinical candidate with which to treat crizotinib-sensitive and resistant ALK-positive NSCLC patients. Further clinical investigation on this compound or the related derivatives is eagerly awaited.
compound a substrate for glucuronidation. Consequently, further structural modification was conducted by neutral replacements in this tail to potentially improve the metabolic stability. These efforts ultimately led to the discovery of 8e as a highly promising candidate for further investigation. The compound contains two hydroxyl moieties that were demonstrated to interact with glycine1201 (G1201) and aspartic acid1203 (D1203) through hydrogen bonds in an 8e−ALK cocrystal complex, respectively, making a considerable contribution to the improved ALK inhibitory activity. Compound 8e displayed strong inhibition against the ALKWT and a panel of the crizotinib-resistance related mutants, including L1196M, G1269A, S1206Y, C1156Y, Y1174L, L1152R, and 1151Tins, with IC50 values of 0.8, 6.6, 9.0, 4.5, 0.6, 0.2, 3.5, and 24 nM, respectively, 67- to 797-fold more potent than crizotinib. It showed excellent kinase selectivity in a kinase-profile study against a diverse panel of 207 kinases, and it also demonstrated approximately 20−150 times greater antiproliferative activity than crizotinib against a number of drug-sensitive or drug-resistant cancer cells with ALK rearrangement, with IC50 values between 0.8 and 24 nM. Compound 8e demonstrates good pharmacokinetics with an oral bioavailability of 86% in the rat. However, the moderate-tohigh in vivo plasma clearance and moderate degree of distribution led to a relatively short half-life in the rat. Further in vivo efficacy studies demonstrated that 8e robustly inhibits tumor growth without obvious toxicity in a crizotinib-resistant (H3122L1196M) xenograft model. These data support 8e as an attractive candidate for further clinical investigation. Given the merging unmet clinical needs, much effort has been devoted to the discovery of a new generation inhibitors with the capability of suppressing the crizotinib-resistant ALK mutants. Several compounds have been advanced to different stages of clinical trials, among which LDK378 was granted a “Breakthrough Therapy” designation in March 2013 by U.S.
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AUTHOR INFORMATION
Corresponding Author
*Phone: +86-20-32015276. Fax: +86-20-32015299. E-mail:
[email protected].
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REFERENCES
(1) Hallber, B.; Palmer, R. H. Mechanistic insight into ALK receptor tyrosinee kinase in human cancer biology. Nat. Rev. Cancer 2013, 13, 685−700. (2) (a) Solomon, B.; Wilner, K. D.; Shaw, A. T. Current status of target therapy for anaplastic lymphoma kinase-rearranged non-small cell lung cancer. Clin. Pharm. Ther. 2014, 95, 15−23.
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(3) Choi, Y. L.; Soda, M.; Yamashita, Y.; Ueno, T.; Takashima, J.; Nakajima, T.; Yatabe, Y.; Takeuchi, K.; Hamada, T.; Haruta, H.; Ishikawa, Y.; Kimura, H.; Mitsudomi, T.; Tanio, Y.; Mano, H. EML4ALK mutations in lung cancer that confer resistance to ALK inhibitors. N. Engl. J. Med. 2010, 363, 1734−1739. (4) Huang, Q. H.; Johnson, T. W.; Bailey, S.; Brooun, A.; Bunker, K. D.; Burke, B. J.; Collins, M. R.; Cook, A. S.; Cui, J. J.; Dack, K. N.; Deal, J. G.; Deng, Y. L.; Dinh, D.; Engstrom, L. D.; He, M. Y.; Hoffman, J.; Hoffman, R. L.; Johnson, P. S.; Kania, R. S.; Lam, H.; Lam, J. L.; Le, P. T.; Li, Q. H.; Lingardo, L.; Liu, W.; Lu, M. W.; McTigue, M.; Palmer, C. L.; Richardson, P. F.; Sach, N. W.; Shen, H.; Smeal, T.; Smith, G. L.; Stewart, A. E.; Timofeevski, S.; Tsaparikos, K.; Wang, H.; Zhu, H. C.l Zhu, J. J.; Zou, H. Y.; Edwards, M. P. The design of potent and selective inhibitors to overcome clinical ALK mutations resistant to crizotinib. J. Med. Chem. 2014, DOI: 10.1021/ jm401805h. (5) Seto, T.; Kiura, K.; Nishio, M.; Nakagawa, K.; Maemondo, M.; Inoue, A.; Hida, T.; Yamamoto, N.; Yoshioka, H.; Harada, M.; Ohe, Y.; Nogami, N.; Takeuchi, K.; Shimada, T.; Tanaka, T.; Tamura, T. CH5424802 (RO5424802) for patients with ALK-rearranged advanced non-small-cell lung cancer (AF-001JP study): a single-arm, open-label, phase 1−2 study. Lancet Oncol. 2013, 14, 590−598. (6) Ariad. http://www.ariad.com. (7) Awad, M. M.; Katayama, R.; McTigue, M.; Liu, W.; Deng, Y.-L.; Brooun, A.; Friboulet, L.; Huang, D.; Falk, M. D.; Timofeevski, S.; Wilner, K. D.; Lockerman, E. L.; Khan, T. M.; Mahmood, S.; Gainor, J. F.; Digumarthy, S. R.; Stone, J. R.; Mino-Kenudson, M.; Christensen, J. G.; Iafrate, J.; Engelman, J. A.; Shaw, A. T. Acquired resistant to crizotinib from a mutation in CD74-ROS1. N. Engl. J. Med. 2013, 368, 2395−2401.
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