2. Academic Validation
  3. New Preclinical Development of a c-Met Inhibitor and Its Combined Anti-Tumor Effect in c-Met-Amplified NSCLC

New Preclinical Development of a c-Met Inhibitor and Its Combined Anti-Tumor Effect in c-Met-Amplified NSCLC

  • Pharmaceutics. 2020 Feb 3;12(2):121. doi: 10.3390/pharmaceutics12020121.
Nam Ah Kim 1,  Sungyoul Hong 2,  Ki Hyun Kim 1,  Du Hyung Choi 3,  Joo Seok Kim 4,  Kyung Eui Park 5,  Jun Young Choi 5,  Young Kee Shin 4 5 6,  Seong Hoon Jeong 1
Affiliations

Affiliations

  • 1 College of Pharmacy, Dongguk University-Seoul, Gyeonggi 10326, Korea.
  • 2 Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Korea.
  • 3 Department of Pharmaceutical Engineering, Inje University, Gyeongnam 50834, Korea.
  • 4 Department of Pharmacy, College of Pharmacy, Seoul National University, Seoul 08826, Korea.
  • 5 R&D Center, ABION Inc., Seoul 08394, Korea.
  • 6 Department of Molecular Medicine and Biopharmaceutical Sciences, Seoul National University, Seoul 08826, Korea.
PMID: 32028611 DOI: 10.3390/pharmaceutics12020121
Abstract

c-Met is a receptor tyrosine kinase with no commercially available product despite being a pivotal target in Cancer progression. Unlike Other c-Met inhibitors that fail clinically, ABN401 is a newly synthesized c-Met inhibitor that is not potentially degraded by aldehyde oxidase (AO) in human liver cytosol. This study aimed to determine the physicochemical stability, pharmacokinetics in beagle dogs, and therapeutic effect of ABN401 in a c-Met-amplified non-small-cell lung Cancer (NSCLC) patient-derived xenograft (PDX) model. ABN401 was found to be a weak basic compound, with PKA and log P values of 7.49 and 2.46, respectively. It is poorly water-soluble but soluble at acidic pH. The accelerated storage stability is dependent on temperature, but the purity remains at over 97% after 6 months. The bioavailability is approximately 30% in dogs and it is highly efficient in the PDX model, achieving around 90% tumor growth inhibition in combination with erlotinib. These observations indicate that the compound is acceptable for the next phase of trials.

Keywords

NSCLC; PDX; bioavailability; c-Met tyrosine kinase inhibitor; poorly water-soluble.

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