2. Academic Validation
  3. Discovery of A-910, a Highly Potent and Orally Bioavailable Dual MerTK/Axl-Selective Tyrosine Kinase Inhibitor

Discovery of A-910, a Highly Potent and Orally Bioavailable Dual MerTK/Axl-Selective Tyrosine Kinase Inhibitor

  • J Med Chem. 2024 Oct 10;67(19):17000-17032. doi: 10.1021/acs.jmedchem.4c01450.
Yiyun Yu 1,  Miyeon Jang 2,  Julie Miyashiro 1,  Richard F Clark 1,  Gui-Dong Zhu 1,  Jane Gong 1,  Yujia Dai 1,  Robin R Frey 1,  Thomas D Penning 1,  Hadong Kim 2,  Hyung Ki Lee 2,  Jin Kwan Kim 2,  Ki Moon Ryu 2,  Seong Jin Park 2,  Taeyoung Yoon 2,  Tao Li 1,  Matthew D Kurnick 1,  Nicolas J Kapecki 1,  Leiming Li 1,  Jacob V Gorman 1,  Debra A Montgomery 1,  Vlasios Manaves 1,  Kenneth D Bromberg 1,  Stella Z Doktor 1,  Ashish Thakur 1,  Jin Wang 1,  Heath A Smith 1,  Fritz G Buchanan 1,  Debra C Ferguson 1,  Maricel Torrent 1,  Clarissa G Jakob 1,  Wei Qiu 1,  Anup K Upadhyay 1,  Ruth L Martin 1,  Albert Lai 1,  Michael R Michaelides 1
Affiliations

Affiliations

  • 1 Abbvie, Inc, 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
  • 2 Dong-A ST, 21, Geumhwa-ro, 105beon-gil, Giheung-gu, Yongin-si, Gyeonggi-do 17073, Korea.
PMID: 39283694 DOI: 10.1021/acs.jmedchem.4c01450
Abstract

TAM Receptor Tyrosine Kinases have emerged as promising therapeutic targets for Cancer treatment due to their roles in both tumor intrinsic survival mechanisms and suppression of antitumor immunity within the tumor microenvironment. Inhibiting MerTK and Axl selectively is believed to hinder Cancer cell survival, reverse the protumor myeloid phenotype, and suppress efferocytosis, thereby eliciting an antitumor immune response. In this study, we present the discovery of A-910, a highly potent and selective dual MerTK/Axl Inhibitor, achieved through a structure-based medicinal chemistry campaign. The lead compound exhibits favorable oral bioavailability, exceptional kinome selectivity, and significantly improved in vivo target engagement. These findings support the use of A-910 as an orally bioavailable in vivo tool compound for investigating the immunotherapy potential of dual MerTK/Axl inhibition.

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