2. Academic Validation
  3. Discovery of Brigatinib (AP26113), a Phosphine Oxide-Containing, Potent, Orally Active Inhibitor of Anaplastic Lymphoma Kinase

Discovery of Brigatinib (AP26113), a Phosphine Oxide-Containing, Potent, Orally Active Inhibitor of Anaplastic Lymphoma Kinase

  • J Med Chem. 2016 May 26;59(10):4948-64. doi: 10.1021/acs.jmedchem.6b00306.
Wei-Sheng Huang 1,  Shuangying Liu 1,  Dong Zou 1,  Mathew Thomas 1,  Yihan Wang 1,  Tianjun Zhou 1,  Jan Romero 1,  Anna Kohlmann 1,  Feng Li 1,  Jiwei Qi 1,  Lisi Cai 1,  Timothy A Dwight 1,  Yongjin Xu 1,  Rongsong Xu 1,  Rory Dodd 1,  Angela Toms 1,  Lois Parillon 1,  Xiaohui Lu 1,  Rana Anjum 1,  Sen Zhang 1,  Frank Wang 1,  Jeffrey Keats 1,  Scott D Wardwell 1,  Yaoyu Ning 1,  Qihong Xu 1,  Lauren E Moran 1,  Qurish K Mohemmad 1,  Hyun Gyung Jang 1,  Tim Clackson 1,  Narayana I Narasimhan 1,  Victor M Rivera 1,  Xiaotian Zhu 1,  David Dalgarno 1,  William C Shakespeare 1
Affiliations

Affiliation

  • 1 ARIAD Pharmaceuticals, Inc. , 26 Landsdowne Street, Cambridge, Massachusetts 02139, United States.
PMID: 27144831 DOI: 10.1021/acs.jmedchem.6b00306
Abstract

In the treatment of echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase positive (ALK+) non-small-cell lung Cancer (NSCLC), secondary mutations within the ALK kinase domain have emerged as a major resistance mechanism to both first- and second-generation ALK inhibitors. This report describes the design and synthesis of a series of 2,4-diarylaminopyrimidine-based potent and selective ALK inhibitors culminating in identification of the investigational clinical candidate brigatinib. A unique structural feature of brigatinib is a phosphine oxide, an overlooked but novel hydrogen-bond acceptor that drives potency and selectivity in addition to favorable ADME properties. Brigatinib displayed low nanomolar IC50s against native ALK and all tested clinically relevant ALK mutants in both enzyme-based biochemical and cell-based viability assays and demonstrated efficacy in multiple ALK+ xenografts in mice, including Karpas-299 (anaplastic large-cell lymphomas [ALCL]) and H3122 (NSCLC). Brigatinib represents the most clinically advanced phosphine oxide-containing drug candidate to date and is currently being evaluated in a global phase 2 registration trial.

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