AXL inhibitors(AXL receptor tyrosine kinase inhibitors), Serine/threonine-protein kinase Aurora inhibitors, TYRO3 inhibitors(TYRO3 protein tyrosine kinase inhibitors)

+ [1]

Therapeutic Areas

Neoplasms

Active Indication-

Inactive Indication

Neoplasms

Originator Organization

Lead Discovery Center GmbH

Active Organization-

Inactive Organization

Max-Planck-Innovation GmbH

Drug Highest PhasePendingPreclinical

First Approval Date-

Regulation-

100 Clinical Results associated with LDC-1267

100 Translational Medicine associated with LDC-1267

100 Patents (Medical) associated with LDC-1267

Literatures (Medical) associated with LDC-1267

01 Mar 2022·Molecular Cancer Research

Bemcentinib and Gilteritinib Inhibit Cell Growth and Impair the Endo-Lysosomal and Autophagy Systems in an AXL-Independent Manner

Article

Author: Zdżalik-Bielecka, Daria ; Jastrzębski, Kamil ; Kozik, Kamila ; Jakubik, Marta ; Miączyńska, Marta ; Poświata, Agata

AbstractAXL, a receptor tyrosine kinase from the TAM (TYRO3 AXL and MER) subfamily, and its ligand growth arrest-specific 6 (GAS6) are implicated in pathogenesis of a wide array of cancers, acquisition of resistance to diverse anticancer therapies and cellular entry of viruses. The continuous development of AXL inhibitors for treatment of patients with cancer and COVID-19 underscores the need to better characterize the cellular effects of AXL targeting.In the present study, we compared the cellular phenotypes of CRISPR–Cas9-induced depletion of AXL and its pharmacological inhibition with bemcentinib, LDC1267 and gilteritinib. Specifically, we evaluated GAS6–AXL signaling, cell viability and invasion, the endo-lysosomal system and autophagy in glioblastoma cells. We showed that depletion of AXL but not of TYRO3 inhibited GAS6-induced phosphorylation of downstream signaling effectors, AKT and ERK1/2, indicating that AXL is a primary receptor for GAS6. AXL was also specifically required for GAS6-dependent increase in cell viability but was dispensable for viability of cells grown without exogenous addition of GAS6. Furthermore, we revealed that LDC1267 is the most potent and specific inhibitor of AXL activation among the tested compounds. Finally, we found that, in contrast to AXL depletion and its inhibition with LDC1267, cell treatment with bemcentinib and gilteritinib impaired the endo-lysosomal and autophagy systems in an AXL-independent manner.Implications:Altogether, our findings are of high clinical importance as we discovered that two clinically advanced AXL inhibitors, bemcentinib and gilteritinib, may display AXL-independent cellular effects and toxicity.

01 Jan 2020·Evidence-Based Complementary and Alternative MedicineQ4 · MEDICINE

Tyrosine Kinase Receptors Axl and MerTK Mediate the Beneficial Effect of Electroacupuncture in a Cuprizone‐Induced Demyelinating Model

Q4 · MEDICINE

ArticleOA

Author: Wang, Yumeng ; Kang, Zheng ; Zhu, Keying ; Wang, Jun ; Sun, Jingxian ; Zhao, Hui ; Zou, Zaofeng

Electroacupuncture has been shown to promote remyelination in a demyelinating model of multiple sclerosis (MS) through enhanced microglial clearance of degraded myelin debris. However, the mechanisms involved in this process are yet to be clearly elucidated. It has been revealed that TAM receptor tyrosine kinases (Tyro3, Axl, and MerTK) play pivotal roles in regulating multiple features of microglia, including the phagocytic function and myelin clearance. Therefore, the aim of this study is to further confirm whether electroacupuncture improves functional recovery in this model and to characterise the involvement of the TAM receptor during this process. In addition to naive control mice, a cuprizone‐induced demyelinating model was established, and long‐term electroacupuncture treatment was administrated. To evaluate the efficiency of functional recovery following demyelination, we performed beam‐walking test and rotarod performance test; to objectify the degree of remyelination, we performed transmission electron microscopy and protein quantification of mature oligodendrocyte markers. Oil Red O staining was used to evaluate the deposit of myelin debris. We confirmed that, in cuprizone‐treated mice, electroacupuncture significantly ameliorates motor‐coordinative dysfunction and counteracts demyelinating processes, with less deposit of myelin debris accumulating in the corpus callosum. Surprisingly, mRNA expression of TAM receptors was significantly upregulated after electroacupuncture treatment, and we further confirmed an increased protein expression of Axl and MerTK after electroacupuncture treatment, indicating their involvement during electroacupuncture treatment. Finally, LDC1267, a selective TAM kinase inhibitor, abolished the therapeutic effect of electroacupuncture on motor‐coordinative dysfunction. Overall, our data demonstrate that electroacupuncture could mitigate the progression of demyelination by enhancing the TAM receptor expression to facilitate the clearance of myelin debris. Our results also suggest that electroacupuncture may be a potential curative treatment for MS patients.

100 Deals associated with LDC-1267

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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Preclinical	-	Max-Planck-Innovation GmbH	-

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