Discovery of AB801, a Potent and Selective Inhibitor of AXL Receptor Tyrosine Kinase for Use in Cancer Therapy

AXL receptor tyrosine kinase (AXL), a transmembrane protein highly expressed in a variety of cancers, has been implicated in the development of resistance to various forms of therapy and poor patient outcomes. Although several strategies have been postulated to limit AXL signaling and thus tumor growth, further refinement is possible. In this Drug Annotation, we report the structure-based design, SAR-driven optimization, preclinical pharmacokinetics (PK), and synthetic chemistry which enabled the discovery of AB801. AB801 is a novel, highly potent, selective, and orally bioavailable AXL inhibitor. In addition to its characterization in a variety of <i>in vitro</i> assays and <i>in vivo</i> studies, AB801 was recently dosed in healthy volunteers and is currently being evaluated clinically as a single agent in advanced solid tumors and in combination with chemotherapy for the treatment of nonsmall cell lung cancer (NSCLC).

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Publication Details

Journal
Journal of Medicinal Chemistry
Published
2025-05-23
DOI
https://doi.org/10.1021/acs.jmedchem.5c00239
Primary Topic
Phagocytosis and Immune Regulation
Type
article
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article

Discovery of AB801, a Potent and Selective Inhibitor of AXL Receptor Tyrosine Kinase for Use in Cancer Therapy

Balint Gal, Ehesan U. Sharif, Lixia Jin, Manjunath Lamani et al.
Journal of Medicinal Chemistry
Phagocytosis and Immune Regulation
article

Discovery of AB801, a Potent and Selective Inhibitor of AXL Receptor Tyrosine Kinase for Use in Cancer Therapy

Balint Gal, Ehesan U. Sharif, Lixia Jin, Manjunath Lamani, Corinne N. Foley, Elaine Ginn, Ester Fernández‐Salas, Pradeep Nareddy, Lian Zhou, Joice Thomas, Xiaoning Zhao, Srinivas Reddy Paladugu, Manmohan R. Leleti, Stefan G. Shaqfeh, Joel W. Beatty, Dillon H. Miles, Rebecca Grange, Jay P. Powers, Yue Tong Lee, Lilian Adeojo, Ada Chen, Jeremy J. Johnson, Hema Singh, Susan L. Paprcka, David Green, Gang Zhao, Hsin‐Ting Huang, Shiwei Qu
article en

Abstract

AXL receptor tyrosine kinase (AXL), a transmembrane protein highly expressed in a variety of cancers, has been implicated in the development of resistance to various forms of therapy and poor patient outcomes. Although several strategies have been postulated to limit AXL signaling and thus tumor growth, further refinement is possible. In this Drug Annotation, we report the structure-based design, SAR-driven optimization, preclinical pharmacokinetics (PK), and synthetic chemistry which enabled the discovery of AB801. AB801 is a novel, highly potent, selective, and orally bioavailable AXL inhibitor. In addition to its characterization in a variety of <i>in vitro</i> assays and <i>in vivo</i> studies, AB801 was recently dosed in healthy volunteers and is currently being evaluated clinically as a single agent in advanced solid tumors and in combination with chemotherapy for the treatment of nonsmall cell lung cancer (NSCLC).

Journal of Medicinal ChemistryVol. 68(11)
Good health and well-being
Openalex Percentile: Top 87%
Phagocytosis and Immune Regulation
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