Publication: Design and Optimization of DAAP ALK Inhibitors

Zhang P*#, Dong J, Zhong B et al. Design and Synthesis of novel 3-sulfonylpyrazol-4-aminopyrimidines as potent anaplastic lymphoma kinase (ALK) inhibitors. Bioorg Med Chem Letters 2016;26(8):1910-18

*Department of Applied Chemistry, Beijing Institute of Technology, Zhongguancun South Street, Beijing
#Beijing Pearl Biotech Ltd, No. 203, Section 2, Wangjing Lize Zhongyuan, Chaoyang District, Beijing

Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase belonging to the insulin receptor superfamily. ALK kinase fusion genes have been identified in cancers such as NSCLC, therefore attracting interest in ALK as a promising antitumor drug target.

While inhibitors targeting ALK have been approved for treatment, their use results in drug resistance. This has led to the continued search for new agents to target both ALK and drug resistant disease.

Our previous publication detailed the discovery of a novel series of 2-arylamino-4-pyrazolamino pyrimidines as potent ALK inhibitors. This paper looks at further SAR exploration and optimization of the novel 3-sulfonylpyrazol-4-amino pyrimidine scaffold.

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  • Our investigation on the effects of substitution at the gate keeper area, the modification of the pyrazole motif, and further optimization of the left piperidine, aiming to improve the potency and drug-like properties of previously reported ALK inhibitors.
  • How this work led to the development of a compound with good DMPK properties and with improved hERG tolerability.
  • That this compound has very good in vitro/in vivo antitumor efficacy (including against an EML-ALK NSCLC xenograft) and is under evaluation as a potential preclinical candidate.

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