KW-2449 / Kyowa Kirin - LARVOL DELTA

Molecular Dynamics-Guided Design and Chemoproteomic Profiling of Covalent Kinase Activity Probes. (PubMed, bioRxiv) - "Chemoproteomic profiling of this probe and a clinical candidate sharing the same indazole core, KW-2449, identified kinase and non-kinase target profiles that differ from recombinant protein assay profiles, underscoring the utility of native kinase profiling in situ...Finally, focused proteomics, kinetic modeling, and molecular dynamics simulations revealed that K60P, as well as the comparator probe XO44, preferentially engage with target kinases in their active, DFG-in conformations, which is driven by increasing population of reaction-ready small molecule conformation. These results together establish a computational and kinetic modeling framework for designing covalent activity probes and highlight the balance of target selectivity and kinetic efficiency as a key factor in determining their proteome-wide reactivity."

Journal • ABL1

KW-2449 Ameliorates Cardiac Dysfunction in a Rat Model of Sepsis-Induced Cardiomyopathy. (PubMed, Inflammation) - "KW-2449 reduced systemic inflammation, cardiac inflammation, and improved cardiac dysfunction in the CLP-induced SIC rat model. The underlying mechanism of the cardio-protective role of KW-2449 in the CLP-induced SIC might be related to Pparα."

Journal • Preclinical • Cardiomyopathy • Cardiovascular • Hepatology • Immunology • Infectious Disease • Inflammation • Liver Failure • Septic Shock • Systemic Inflammatory Response Syndrome • PPARA

Inhibition of the FLT3 Kinase Signaling Pathway in Neuron Stimulates KCC2 Expression and Suppresses Seizure (AES 2024) - "Our group's previous high-throughput drug screening work led to the unexpected discovery that a number of small molecule FLT3 inhibitor compounds (FLT3i), including KW-2449 and Sunitinib, stimulate the gene expression of chloride transporter KCC2 in neurons. Taken together, our results reveal previously unknown roles of FLT3 signaling in promoting neuronal functional maturation and suppressing neuroinflammation, indicating that FLT3 kinase signaling modulates a transcriptional program that plays critical roles in brain development and health, providing a promising novel therapeutic target for the treatment of epilepsy."

Autism Spectrum Disorder • CNS Disorders • Epilepsy • Genetic Disorders • Hematological Malignancies • Leukemia • Oncology • FLT3 • PTEN

Identification of KW-2449 as a dual inhibitor of ferroptosis and necroptosis reveals that autophagy is a targetable pathway for necroptosis inhibitors to prevent ferroptosis. (PubMed, Cell Death Dis) - "This study provides the first understanding of how necroptosis inhibitors can prevent ferroptosis and suggests that autophagy is a targetable pathway for necroptosis inhibitors to prevent ferroptosis. Therefore, the identification and design of pharmaceutical molecules that target the autophagy pathway from necroptosis inhibitors is a promising strategy to develop dual inhibitors of necroptosis and ferroptosis in clinical application."

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Identification of novel neuroprotectants against vincristine-induced neurotoxicity in iPSC-derived neurons. (PubMed, Cell Mol Life Sci) - "Six compounds showed favorable pharmacological profiles - AZD7762, A-674563, Blebbistatin, Glesatinib, KW-2449, and Pelitinib, all novel neuroprotectants against vincristine toxicity to neurons. In this study, we utilized high-throughput screening of a large library of compounds in a therapeutically relevant assay. We identified several novel compounds that are efficacious in protecting different neuronal subtypes from the toxicity induced by a common chemotherapeutic agent, vincristine which could have therapeutic potential in the clinic."

Journal • Breast Cancer • CNS Disorders • Hematological Malignancies • Leukemia • Oncology • Osteosarcoma • Pain • Sarcoma • Solid Tumor

Identification of novel neuroprotectants against vincristine-induced neurotoxicity in iPSC-derived neurons. (PubMed, Res Sq) - "Six compounds showed favorable pharmacological profiles - AZD7762, A-674563, Blebbistatin, Glesatinib, KW-2449, and Pelitinib, all novel neuroprotectants against vincristine toxicity to neurons. In this study, we utilized high-throughput screening of a large library of compounds in a therapeutically relevant assay. We identified several novel compounds that are efficacious in protecting different neuronal subtypes from the toxicity induced by a common chemotherapeutic agent, vincristine which could have therapeutic potential in the clinic."

Journal • Breast Cancer • CNS Disorders • Hematological Malignancies • Leukemia • Oncology • Osteosarcoma • Pain • Sarcoma • Solid Tumor

KW2449 ameliorates collagen-induced arthritis by inhibiting RIPK1-dependent necroptosis. (PubMed, Front Immunol) - "These findings suggest that the overexpression of RIPK1 is positively correlated with the severity of RA. KW2449, as a small molecule inhibitor targeting RIPK1, has the potential to be a therapeutic strategy for RA treatment by inhibiting RIPK1-dependent necroptosis."

Journal • Immunology • Inflammation • Inflammatory Arthritis • Rheumatoid Arthritis • Rheumatology • RIPK1

KW-2449 and VPA exert therapeutic effects on human neurons and cerebral organoids derived from MECP2-null hESCs. (PubMed, Stem Cell Res Ther) - "These findings suggest that KW-2449 and VPA might be promising drugs for RTT treatment."

Journal • CNS Disorders • Developmental Disorders • Movement Disorders • Psychiatry

Novel Small Molecule Compounds for Treating Epilepsy Through Activation of KCC2 Expression (AES 2021) - "The small-molecule compounds described in our study may have therapeutic effects not only in RTT but also in other neurological disorders, such as many epileptic disorders, involving dysregulation of KCC2."

CNS Disorders • Developmental Disorders • Epilepsy • Movement Disorders • Oncology • FLT3

The multitargeted kinase inhibitor KW-2449 ameliorates cisplatin-induced nephrotoxicity by targeting RIPK1-mediated necroptosis. (PubMed, Biochem Pharmacol) - "Oral administration of KW-2449 attenuated renal cell necrosis and reduced pro-inflammatory responses in mouse models of cisplatin-induced nephrotoxicity. Taken together, our study shows that KW-2449 is a novel necroptosis inhibitor by targeting RIPK1 kinase activity and has great clinic potential for the treatment of cisplatin-induced nephrotoxicity."

Journal • Inflammation • Oncology • RIPK1

[VIRTUAL] The Combined Treatment with the FLT3-Inhibitor AC220 and the Complex I Inhibitor Iacs-010759 Synergistically Depletes Wt- and FLT3-Mutated Acute Myeloid Leukemia Cells (ASH 2020) - "1C) are known FLT3 (FMS-like tyrosine kinase 3) inhibitors, including AC220 (quizartinib), dovitinib, nintedanib, SGI-1776, and rebastinib, pointing to a molecular target of great potential interest in the design of synergistic drug combinations with IACS-010759. Thus, we investigated more in-depth the synergism between IACS-010759 (10nM) and 13 FLT3 inhibitors, all currently in clinical trials (AC220, sorafenib, gilteritinib, sunitinib, ponatinib, midostaurin, ibrutinib, TP-0903, crenolanib, tandutinib, FF-10101, lestaurtinib, and KW-2449; 0.0128:5x:5000nM), in AML cell lines (FLT3-wt KG-1, U937, OCI-AML2, OCI-AML3; and FLT3-mutant MOLM-13 and MOLM-14)...Influx inhibition of both the two main carbon sources, glucose and glutamine, was observed leading to impairment of the TCA cycle and glycolysis for energy production, as well as pentose phosphate pathway and de novo nucleotide biosynthesis. In conclusion, we identified a novel drug combination AC220 and IACS-010759..."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Metabolic Disorders • Oncology • FLT3

Anti-Inflammatory Effect of KW-2449 on Autoimmune Encephalomyelitis: An Experimental Study on Mice. (PubMed, Endocr Metab Immune Disord Drug Targets) - "The KW-2449, aging as a multi-kinase inhibitor, modulates the inflammatory responses of cytokine cascades either in brain or in plasma and reduces EAE pathogenesis manifestation."

Journal • CNS Disorders • Immune Modulation • Immunology • Inflammation • Multiple Sclerosis • AURKA • CCL2 • FLT3 • IL6 • MMP2 • TNFA

Pharmacological enhancement of KCC2 gene expression exerts therapeutic effects on human Rett syndrome neurons and Mecp2 mutant mice. (PubMed, Sci Transl Med) - "Injection of KEEC KW-2449 or piperine in Mecp2 mutant mice ameliorated disease-associated respiratory and locomotion phenotypes. The small-molecule compounds described in our study may have therapeutic effects not only in RTT but also in other neurological disorders involving dysregulation of KCC2."

Journal • CNS Disorders • Developmental Disorders • Psychiatry

Safety, tolerability, and pharmacokinetic/pharmacodynamic study of KW-2449 in acute myelogenous leukemia (AML) (Protocol Number: 2449-US-002) (clinicaltrials.gov) - P1/2, N=14; Terminated; Completion date: May ’10 → Dec ’10

Hematological Malignancies • Oncology

The Identification of Novel Epigenetic Therapies for ALK-Driven Haematological Malignancies (ASH 2019) - "Results Several of the validated drugs have previously been used/trialled in the clinic for the treatment of various cancers, e.g. aurora kinase (XL-228), topoisomerase (Mitoxantrone HCl) and HDAC (Romidepsin) inhibitors – these functioned as internal controls for the drug screens. However, an assortment of novel drugs was also identified that have not previously been described in the context of the treatment of ALK-driven haematological malignancies; including the FLT3 inhibitor KW2449 which caused a >75% decrease in viability in all the tested cell lines and as such may serve as a novel front line therapy...Furthermore, we investigated the combinatorial potential of the identified DNMT inhibitor with ALK TKIs such as Brigatinib and observed the inhibitor acting synergistically (as per Bliss-Independence calculations) resulting in a further decrease in cell viability...Data reveal a potent inhibitor of DNA methylation as a candidate drug that suppresses the growth of..."

ALK • FLT3

PTEN deficiency confers colorectal cancer cell resistance to dual inhibitors of FLT3 and aurora kinase A. (PubMed, Cancer Lett) - "From a synthetic lethality drug screen with PTEN-isogenic colorectal cancer cells, we found that mutant-PTEN cells were resistant to dual inhibitors of FLT3 and aurora kinase-A, including KW2449 and ENMD-2076. Co-treatment with the inhibitors of its upstream signaling completely abolished the reactivation of AKT phosphorylation by KW2449 and reversed the drug resistant phenotype. These data suggest that reactivation of AKT phosphorylation at Ser473 is a key factor to confer drug resistant phenotype of mutant-PTEN cells to the dual inhibitors and that proper drug combinations that shut down AKT reactivation is necessary for the effective treatment of mutant-PTEN cancer with the dual inhibitors in clinical settings."

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Evaluation of Protein Kinase Inhibitors with PLK4 Cross-Over Potential in a Pre-Clinical Model of Cancer. (PubMed, Int J Mol Sci) - "Here, we examined an array of PK inhibitors (CFI-400945, CFI-400437, centrinone, centrinone-B, R-1530, axitinib, KW-2449, and alisertib) for their potential crossover to PLK4 by comparative structural docking and activity inhibition in multiple established embryonal tumor cell lines (MON, BT-12, BT-16, DAOY, D283). (3) KW-2449, R-1530 and axitinib are the ones predicted to have moderate-to-good brain penetration. In conclusion, a new selective PLK4 inhibitor with favorable physiochemical properties for optimal brain exposure can be beneficial for the treatment of EBT."

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