Abstract A011: Discovery and characterization of the first highly potent and selective AXL receptor tyrosine kinase inhibitor AB801
Bibliographic record
Abstract
Abstract The AXL receptor (AXL) is a transmembrane protein that is highly expressed in a variety of tumors and correlates with poor prognosis in cancer patients. AXL is expressed in cancer, immune, and stromal cells and has been implicated in the development of resistance to chemotherapy, targeted therapies, and immunotherapies. Activation of AXL by either its ligand, growth arrest specific protein 6 (GAS6), or ligand-independent homo- and hetero-dimerization facilitates AXL phosphorylation and initiates signaling cascades that promote cancer cell proliferation, survival, and an immunosuppressive microenvironment. Historically, most small-molecule inhibitors capable of suppressing AXL signaling are unselective and inhibit several other related kinases. Administration of a truly selective AXL inhibitor would be expected to be free of the off-target toxicity of other kinase inhibitors; this, in turn, might allow the unmasking of the full therapeutic benefit associated with robust AXL inhibition. To this end, we initiated a medicinal chemistry campaign with additional goals of discovering a potent and orally bioavailable inhibitor. Through iterative SAR-guided design we discovered AB801, a reversible AXL inhibitor. Importantly, AB801 exhibits excellent selectivity against MERTK, TYRO3 (closely related tyrosine kinases) and the overall kinome. AB801 exhibits a double-digit picomolar inhibitory constant and retains significant activity in cell-based assays performed in 100% human serum. In vitro, AB801 increases sensitivity to standard of care (SOC) therapeutics such as chemotherapy and results in increased DNA damage, leading to cancer cell death. AB801 treatment also sensitizes tumors to immune checkpoint blockade by increasing immune cell activation. Significant anti-tumor efficacy is observed in combination with SOC therapies in multiple in vivo models. When compared against existing AXL inhibitors such as bemcentinib, AB801 shows large improvements in both potency and selectivity. A placebo-controlled phase 1 study (NCT06004921) to assess the safety and pharmacokinetics of AB801 in healthy volunteers was recently completed; AB801 was well tolerated at all tested doses and exhibited a dose-proportionate increase in exposure. Currently, AB801 is in clinical evaluation in patients with advanced cancer (NCT06120075). Citation Format: Dillon H. Miles, Corinne N. Foley, Shiwei Qu, Dillon H. Miles, Srinivas Paladugu, Ehesan U. Sharif, Joice Thomas, Pradeep Nareddy, Guiling Zhao, Rebecca Grange, Manmohan R. Leleti, Jay P. Powers, Stefan Garrido-Shaqfeh, Ada Chen, Hema Singh, Yue Tong Lee, Xiaoning Zhao, David Green, Hsin-Ting Huang, Lixia Jin, Jhansi Leslie, Logan Chinn, Susan L Paprcka, Ester Fernandez-Salas. Discovery and characterization of the first highly potent and selective AXL receptor tyrosine kinase inhibitor AB801 [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Optimizing Therapeutic Efficacy and Tolerability through Cancer Chemistry; 2024 Dec 9-11; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(12_Suppl):Abstract nr A011.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".