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2ms
AXL and SHC1 confer crizotinib resistance in patient-derived xenograft model of ALK-driven lung cancer. (PubMed, iScience)
To discover therapeutic targets to overcome crizotinib resistance (CR), we generated patient-derived xenograft CR mice and subjected them to phosphorylation profiling, together with CR mice treated with ASP3026 or alectinib. We also found that SHC1 phosphorylation was increased in CR mice and SHC1 knockdown sensitized ALK-driven cells to crizotinib. Our study provides a new view of signaling pathways leading to CR, suggesting AXL and SHC1 as potential targets for combination therapy to overcome CR.
Preclinical • Journal
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ALK (Anaplastic lymphoma kinase) • AXL (AXL Receptor Tyrosine Kinase)
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ALK rearrangement
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Xalkori (crizotinib) • Alecensa (alectinib) • ASP-3026
5ms
Structure-guided conversion from an anaplastic lymphoma kinase inhibitor into Plasmodium lysyl-tRNA synthetase selective inhibitors. (PubMed, Commun Biol)
ASP3026, an anaplastic lymphoma kinase (ALK) inhibitor was recently identified as a novel Plasmodium falciparum LysRS (PfLysRS) inhibitor...However, its inhibitory activity against parasites did not improve, suggesting potential future optimization directions. This study presents a new example of derivatization of kinase inhibitors repurposed to inhibit aaRS.
Journal
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ALK (Anaplastic lymphoma kinase)
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ASP-3026
almost4years
Safety and Antitumor Activity of Repeated ASP3026 Administration in Japanese Patients with Solid Tumors: A Phase I Study. (PubMed, Drugs R D)
ASP3026 at a 200-mg dose may provide therapeutic benefit for patients with solid tumors, with a tolerable safety profile.
Clinical • P1 data • Journal
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ALK (Anaplastic lymphoma kinase) • EML4 (EMAP Like 4)
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ALK positive • ALK rearrangement
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ASP-3026
4years
Inhibition of Plasmodium falciparum Lysyl-tRNA synthetase via an anaplastic lymphoma kinase inhibitor. (PubMed, Nucleic Acids Res)
Finally, primary structure-activity relationship analyses indicated that the inhibition of PfLysRS by ASP3026 is highly structure specific. This work not only provides a new chemical scaffold with good druggability for antimalarial development but also highlights the potential for repurposing kinase-inhibiting drugs to tRNA synthetase inhibitors to treat human diseases.
Journal
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ALK (Anaplastic lymphoma kinase)
|
ASP-3026
over4years
Dual inhibition of IGF-IR and ALK as an effective strategy to eradicate NPM-ALK T-cell lymphoma. (PubMed, J Hematol Oncol)
Combined targeting of IGF-IR and ALK is more effective than targeting IGF-IR or ALK alone in NPM-ALK T cell lymphoma. This strategy might also limit emergence of resistance to high doses of ALK inhibitors. Therefore, it could represent a successful therapeutic approach to eradicate this aggressive lymphoma. Importantly, combined inhibition is feasible because of the clinical availability of IGF-IR and ALK inhibitors. Our findings are applicable to other types of cancer where IGF-IR and ALK are simultaneously expressed.
Journal
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ALK (Anaplastic lymphoma kinase) • NPM1 (Nucleophosmin 1)
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ASP-3026 • picropodophyllin (AXL1717)