Discovery of a Potent and Selective Oral Inhibitor of ERK1/2 (AZD0364) That Is Efficacious in Both Monotherapy and Combination Therapy in Models of Nonsmall Cell Lung Cancer (NSCLC)

  • J Med Chem. 2019 Dec 26;62(24):11004-11018. doi: 10.1021/acs.jmedchem.9b01295.
Richard A Ward  1 ,  Mark J Anderton  1 ,  Paul Bethel  2 ,  Jason Breed  1 ,  Calum Cook  1 ,  Emma J Davies  1 ,  Andrew Dobson  2 ,  Zhiqiang Dong  3 ,  Gary Fairley  1 ,  Paul Farrington  4 ,  Lyman Feron  1 ,  Vikki Flemington  1 ,  Francis D Gibbons  5 ,  Mark A Graham  2 ,  Ryan Greenwood  1 ,  Lyndsey Hanson  4 ,  Philip Hopcroft  1 ,  Rachel Howells  1 ,  Julian Hudson ,  Michael James ,  Clifford D Jones ,  Christopher R Jones ,  Yongchao Li  3 ,  Scott Lamont  1 ,  Richard Lewis  6 ,  Nicola Lindsay  1 ,  James McCabe  2 ,  Thomas McGuire  1 ,  Philip Rawlins  1 ,  Karen Roberts  1 ,  Linda Sandin ,  Iain Simpson ,  Steve Swallow  2 ,  Jia Tang  3 ,  Gary Tomkinson  2 ,  Michael Tonge  1 ,  Zhenhua Wang  3 ,  Baochang Zhai  3
Affiliations
  • 1. Oncology and Discovery Sciences R&D , AstraZeneca , Darwin Building and Hodgkin Building, c/o Darwin Building, 310 Cambridge Science Park, Milton Rd , Cambridge CB4 0WG , U.K.
  • 2. Chemical Development, Pharmaceutical Technology & Development , AstraZeneca , Macclesfield Campus, Macclesfield SK10 2NA , U.K.
  • 3. Pharmaron Beijing Co., Ltd. , 6 Taihe Road BDA , Beijing 100176 , P.R. China.
  • 4. Bioscience, Oncology R&D , AstraZeneca , Alderley Park, Macclesfield SK10 4TG , U.K.
  • 5. DMPK, Oncology R&D , AstraZeneca , Waltham , Massachusetts 02451 , United States.
  • 6. Medicinal Chemistry, Respiratory, Inflammation and Autoimmune (RIA), BioPharmaceuticals R&D , AstraZeneca , Gothenburg 431 50 , Sweden.
PMID: 31710489 DOI: 10.1021/acs.jmedchem.9b01295
Abstract

The Ras/MAPK pathway is a major driver of oncogenesis and is dysregulated in approximately 30% of human cancers, primarily by mutations in the BRAF or Ras genes. The extracellular-signal-regulated Kinases (ERK1 and ERK2) serve as central nodes within this pathway. The feasibility of targeting the Ras/MAPK pathway has been demonstrated by the clinical responses observed through the use of BRAF and MEK inhibitors in BRAF V600E/K metastatic melanoma; however, resistance frequently develops. Importantly, ERK1/2 inhibition may have clinical utility in overcoming acquired resistance to Raf and MEK inhibitors, where Ras/MAPK pathway reactivation has occurred, such as relapsed BRAF V600E/K Melanoma. We describe our structure-based design approach leading to the discovery of AZD0364, a potent and selective inhibitor of ERK1 and ERK2. AZD0364 exhibits high cellular potency (IC50 = 6 nM) as well as excellent physicochemical and absorption, distribution, metabolism, and excretion (ADME) properties and has demonstrated encouraging antitumor activity in preclinical models.