LDK378

J. Med. Chem. 2013, DOI:10.1021/jm400402q).

CAS Number:

1032900-25-6

Mol. Formula:

C₂₈H₃₆ClN₅O₃S

MW:

558.13

Novartis investigational drug LDK378, a selective inhibitor of the cancer target anaplastic lymphoma kinase (ALK), shows a marked clinical response in patients with ALK+ non-small cell lung cancer (NSCLC) during the 49th Annual Meeting of the American Society of Clinical Oncology (ASCO) on June 3, 2013.

Doctors and patients are clamoring for more ways to fight lung cancer, the leading cause of cancer deaths in the U.S., of which NSCLC is the most common form. In March, LDK378 received Breakthrough Therapy designation from the US Food and Drug Administration (FDA). The designation is intended to expedite the development and review of drugs that treat life-threatening conditions and show improvement over available therapies.

Currently, two Phase II clinical trials are actively recruiting patients worldwide. One study focuses on patients with ALK+ NSCLC who were previously treated with chemotherapy and crizotinib (NCT01685060). The second study examines LDK378 in patients who are crizotinib-naive (NCT01685138). In addition, Phase III clinical trials are planned to begin in the coming months, aiming to enroll more than 1,100 patients with ALK+ NSCLC at sites worldwide. Novartis plans to file for approval the drug in early 2014.

Chemical Name of LDK378

5-chloro-N2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine

Chemical Synthesis of LDK378

Technical Data of LDK378
1H NMR (400 MHz, DMSO-d6 + trace D2O) δ 8.32 (s,1H), 8.27 (d, 1H), 7.88 (d, 1H), 7.67 (dd, 1H), 7.45 (dd, 1H), 7.42 (s, 1H), 6.79 (s, 1H), 4.56 – 4.48(m, 1H), 3.49 – 3.32 (m, 3H), 3.10 - 2.91 (m, 3H), 2.09 (s, 3H), 1.89 – 1.77 (m, 4H), 1.22 (d, 6H), 1.13 (d, 6H); ESMS m/z 558.1 (M + H+).

The compound LDK378, a highly selective inhibitor of ALK, has been granted “Breakthrough Therapy Designation” by the FDA for the treatment of patients with ALK-positive metastatic non-small cell lung cancer (NSCLC) who have already received treatment with crizotinib (Xalkori).

ClinicalTrials.gov. A Dose Finding Study With Oral LDK378 in Patients With Tumors Characterized by Genetic Abnormalities in Anaplastic Lymphoma Kinase (ALK) (Phase 1). http://www.http://clinicaltrials.gov/show/NCT01283516; Accessed June 7, 2013; currently recruiting participants.

ClinicalTrials.gov. LDK378 in crizotinib naïve adult patients with ALK-activated non-small cell lung cancer (Phase 2). http://www.clinicaltrials.gov/ct2/show/NCT01685138; Accessed June 7, 2013; currently recruiting participants.

ClinicalTrials.gov. LDK378 in adult patients with ALK-activated NSCLC previously treated with chemotherapy and crizotinib (phase 2) http://www.clinicaltrials.gov/ct2/show/NCT01685060; Accessed June 7,2013; currently recruiting participants.

Mehra R, Camidge DR, Sharma S, et al. First-in-human phase I study of the ALK inhibitor LDK378 in advanced solid tumors. J Clin Oncol 30, 2012 (suppl; abstr 3007).

Alice Tsang Shaw, et al., Clinical activity of the ALK inhibitor LDK378 in advanced, ALK-positive NSCLC; 2013 ASCO Annual Meeting; Abstract Number: 8010; Citation: J Clin Oncol 31, 2013 (suppl; abstr 8010)

Tom H. Marsilje, Wei Pei, Bei Chen, Wenshuo Lu, Tetsuo Uno, Yunho Jin, Tao Jiang, Sungjoon Kim, Nanxin Li, Markus Warmuth, Yelena Sarkisova, Fangxian Sun, Auzon Steffy, AnneMarie C. Pferdekamper, Sean B Joseph, Young Kim, Tove Tuntland, Xiaoming Cui, Nathanael S Gray, Ruo Steensma, Yongqin Wan, Jiqing Jiang, Jie Li, Greg Chopiuck, W. Perry Gordon, Allen G Li, Wendy Richmond, Johathan Chang, Todd Groessl, You-Qun He, Bo Liu, Andrew Phimister, Alex Aycinena, Badry Bursulaya, Christian Lee, Donald S Karanewsky, H Martin Seidel, Jennifer L Harris, and Pierre-Yves Michellys, Synthesis, Structure-Activity Relationships and In Vivo Efficacy of the Novel Potent and Selective Anaplastic Lymphoma Kinase (ALK) Inhibitor LDK378 Currently In Phase 1 and 2 Clinical Trials, Journal of Medicinal Chemistry, 2013

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