altiratinib (DCC-2701) / Ono Pharma - LARVOL DELTA

Evaluating the therapeutic potential of novel TrkA agonists in targeting glioblastoma stem cells (GSCs) (AACR 2025) - "Synergy with targeted therapies, including Abemaciclib (a CDK4/6 inhibitor) and Altiratinib (a multi-kinase inhibitor targeting MET, VEGFR2, and Trk pathways), was also evaluated. Ongoing studies aim to further elucidate the mechanisms underlying TrkA modulation and its role in maintaining GSCs in vitro. Additionally, investigations are exploring the potential synergistic effects of TrkA-specific agonists with targeted therapies to enhance GSC susceptibility to treatment."

Late-breaking abstract • Brain Cancer • CNS Tumor • Diffuse Intrinsic Pontine Glioma • Glioblastoma • Oncology • Solid Tumor • KDR • NTRK1 • NTRK2 • NTRK3

Small molecule kinase inhibitor altiratinib inhibits brain cyst forming bradyzoites of Toxoplasma gondii. (PubMed, J Microbiol) - "Bradyzoites were obtained from mouse brain cysts, cultured in ARPE-19 cells, and treated with afatinib and neratinib (HER2/HER4 inhibitors), ACTB-1003 and regorafenib (VEGFR-2 inhibitors), or altiratinib and foretinib (c-MET inhibitors). Altiratinib demonstrated an effect against bradyzoites at the lowest concentration with minimal impact on the host cells. It may be effective in blocking the reactivation of brain cysts in immunodeficiency patients caused by bradyzoites."

Journal • Infectious Disease • ERBB4 • HER-2

Engineering small-molecule analogues of altiratinib via CREB-regulated transcription co-activator 3-target screening for the development of potent and safe topical therapeutics against skin hyperpigmentary diseases. (PubMed, Clin Transl Med) - No abstract available

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Proposal of Foretinib as Second-Line TKI after Capmatinib/Tepotinib Treatment Failure in NSCLC with MET Exon 14 Mutation (IASLC-WCLC 2022) - " Initial screening (300 drugs, including 33 MET-TKIs) was performed using Ba/F3 cells carrying METex14 plus MET D1228A/Y because anecdotal case reports suggested that D1228X mutations were more refractory to second-line MET-TKIs than Y1230X mutations.This screening found four candidate type II MET-TKIs (altiratinib, CEP-40783, foretinib and sitravatinib). We then performed further growth inhibitory assays using these four candidates plus other four MET-TKIs (type Ib; capmatinib and tepotinib, type II; cabozantinib and merestinib) in Ba/F3 cells carrying METex14 plus one of MET D1228A/E/G/H/N/V/Y or Y1230C/D/H/N/S secondary mutations... The type II MET-TKI foretinib may be an appropriate second-line MET-TKI for NSCLCs carrying METex14 after campatinib/tepotinib treatment failure by secondary mutations at D1228 or Y1230 residues.212"

Clinical • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • MET

Altiratinib blocks Toxoplasma gondii and Plasmodium falciparum development by selectively targeting a spliceosome kinase. (PubMed, Sci Transl Med) - "Consistent with the splicing control activity of this kinase family, we have shown that altiratinib can cause global disruption of splicing, primarily through intron retention in both T. gondii and P. falciparum. Thus, our data establish parasitic PRP4K/CLK3 as a potential pan-apicomplexan target whose repertoire of inhibitors can be expanded by the addition of altiratinib."

Journal • Brain Cancer • Glioblastoma • Oncology • Solid Tumor

Foretinib can overcome common on-target resistance mutations after capmatinib/tepotinib treatment in NSCLCs with MET exon 14 skipping mutation. (PubMed, J Hematol Oncol) - "The type II MET-TKI foretinib may be an appropriate second-line treatment for NSCLCs carrying METex14 after campatinib/tepotinib treatment failure by secondary mutations at residue D1228 or Y1230."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • MET

CRTC3, a sensor and key regulator for melanogenesis, as a tunable therapeutic target for pigmentary disorders. (PubMed, Theranostics) - "Furthermore, we identified the therapeutic potential of altiratinib to inhibit melanogenesis in human melanocytes and human skin effectively and safely. CRTC3 appears to be a key sensor for melanogenesis and can be used as a reversible and tunable tool for selectively regulating melanogenesis without affecting melanocyte integrity. Thus, CRTC3 can also serve as a screening tool for the discovery of ideal melanogenesis-modulating small molecules."

Journal • Ophthalmology • KRT14 • MITF • Tyrosinase

NTRK kinase domain mutations in cancer variably impact sensitivity to type I and type II inhibitors. (PubMed, Commun Biol) - "Our study shows that a subset of larotrectinib-resistant NTRK1 mutations (V573M, F589L and G667C) retains sensitivity to altiratinib, while the NTRK1 and xDFG motif NTRK1 mutations are highly sensitive to type II inhibitors, including altiratinib, cabozantinib and foretinib. Moreover, molecular modeling suggests that the introduction of a sulfur moiety in the binding pocket, via methionine or cysteine substitutions, specifically renders the mutant kinase hypersensitive to type II inhibitors. Future precision treatment strategies may benefit from selective targeting of these kinase mutants based on our findings."

Journal • Oncology • NTRK • NTRK1

Combined c-Met/Trk inhibition overcomes resistance to CDK4/6 inhibitors in Glioblastoma. (PubMed, Cancer Res) - "Combining the CDK4/6 inhibitor abemaciclib with the c-Met/Trk inhibitor altiratinib or the corresponding siRNAs induced apoptosis, leading to significant synergy against GBM. Combining the CDK4/6 inhibitor abemaciclib with the c-Met/Trk inhibitor altiratinib or the corresponding siRNAs induced apoptosis, leading to significant synergy against GBM. Collectively, these findings demonstrate that the activation of c-Met/TrkA-B pathways is a novel mechanism involved in therapeutic resistance of GBM to CDK4/6 inhibition and that dual inhibition of c-Met/Trk with CDK4/6 should be considered in future clinical trials."

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