Discovery of A-910, a Highly Potent and Orally Bioavailable Dual MerTK/Axl-Selective Tyrosine Kinase Inhibitor
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 <b>A-910</b>, 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 <b>A-910</b> as an orally bioavailable in vivo tool compound for investigating the immunotherapy potential of dual MerTK/Axl inhibition.
Authors
- Vlasios Manaves
- Miyeon Jang
- Thomas D. Penning (ORCID: https://orcid.org/0000-0003-2287-6735)
- Jacob V. Gorman
- Robin R. Frey (ORCID: https://orcid.org/0009-0007-6116-7436)
- Richard F. Clark (ORCID: https://orcid.org/0000-0002-9350-7526)
- Yi‐Yun Yu (ORCID: https://orcid.org/0000-0001-7786-7284)
- Jin Wang (ORCID: https://orcid.org/0000-0002-5342-729X)
- Ki Moon Ryu
- Albert Lai (ORCID: https://orcid.org/0000-0002-7265-2986)
- Clarissa G. Jakob
- Leiming Li (ORCID: https://orcid.org/0000-0003-2073-6632)
- Nicolas J. Kapecki
- Debra C. Ferguson
- Ruth L. Martin (ORCID: https://orcid.org/0000-0002-0318-5325)
- Matthew D. Kurnick
- F. Gregory Buchanan
- Kenneth D. Bromberg
- Jane Gong
- Hadong Kim
- Anup K. Upadhyay (ORCID: https://orcid.org/0000-0002-7536-2183)
- Jin Kwan Kim
- Julie M. Miyashiro
- Tao Li (ORCID: https://orcid.org/0000-0003-3672-6906)
- Ashish Thakur (ORCID: https://orcid.org/0000-0002-8456-1088)
- Wei Qiu (ORCID: https://orcid.org/0000-0003-1562-9197)
- Michael R. Michaelides (ORCID: https://orcid.org/0000-0001-9435-2389)
- Tae‐young Yoon
- Seong Jin Park (ORCID: https://orcid.org/0000-0002-7859-7439)
- Yujia Dai
- Maricel Torrent
- Gui‐Dong Zhu
- Debra Montgomery
- Hyung Ki Lee
- Heath A. Smith
- Stella Z. Doktor
Institutions
- AbbVie (United States) (US)
- Dong-A ST (South Korea) (KR)
- Dong-A Pharmaceutical (South Korea) (KR)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2024-09-16
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c01450
- Citations
- 8
- Primary Topic
- Phagocytosis and Immune Regulation
- Type
- article
- Field-Weighted Citation Impact
- 1.92