TAM receptors (Tyro-3, Axl, and Mertk) are a family of three homologous type I receptor tyrosine kinases that are implicated in several human malignancies. Overexpression of TAMs and their major ligand Growth arrest-specific factor 6 (Gas6) is associated with more aggressive staging of cancers, poorer predicted patient survival, acquired drug resistance and metastasis. Here we describe small molecule inhibitors (RU-301 and RU-302) that target the extracellular domain of Axl at the interface of the Ig-1 ectodomain of Axl and the Lg-1 of Gas6. These inhibitors effectively block Gas6-inducible Axl receptor activation with low micromolar IC50s in cell-based reporter assays, inhibit Gas6-inducible motility in Axl-expressing cell lines, and suppress H1299 lung cancer tumor growth in a mouse xenograft NOD-SCIDγ model. Furthermore, using homology models and biochemical verifications, we show that RU301 and 302 also inhibit Gas6 inducible activation of Mertk and Tyro3 suggesting they can act as pan-TAM inhibitors that block the interface between the TAM Ig1 ectodomain and the Gas6 Lg domain. Together, these observations establish that small molecules that bind to the interface between TAM Ig1 domain and Gas6 Lg1 domain can inhibit TAM activation, and support the further development of small molecule Gas6-TAM interaction inhibitors as a novel class of cancer therapeutics.
Pharmacology, Toxicology and Pharmaceutical Science
9
10%
Agricultural and Biological Sciences
9
10%
Medicine and Dentistry
5
6%
Chemistry
3
3%
Other
7
8%
Unknown
31
34%
Attention Score in Context
Attention Score in Context
This research output has an Altmetric Attention Score of 16. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 07 June 2022.
All research outputs
#2,759,250
of 31,393,817 outputs
Outputs from Scientific Reports
#24,875
of 170,888 outputs
Outputs of similar age
#41,016
of 333,701 outputs
Outputs of similar age from Scientific Reports
#777
of 4,809 outputs
Altmetric has tracked 31,393,817 research outputs across all sources so far. Compared to these this one has done particularly well and is in the 91st percentile: it's in the top 10% of all research outputs ever tracked by Altmetric.
So far Altmetric has tracked 170,888 research outputs from this source. They typically receive a lot more attention than average, with a mean Attention Score of 18.4. This one has done well, scoring higher than 85% of its peers.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 333,701 tracked outputs that were published within six weeks on either side of this one in any source. This one has done well, scoring higher than 87% of its contemporaries.
We're also able to compare this research output to 4,809 others from the same source and published within six weeks on either side of this one. This one has done well, scoring higher than 83% of its contemporaries.
