KW 2478 / Kyowa Kirin - LARVOL DELTA

KW2478 and Cisplatin Synergistically Anti-colorectal Cancer by Targeting PI3K/AKT/mTOR Pathway. (PubMed, Anticancer Agents Med Chem) - "The combination of KW2478 and cisplatin inhibits colorectal cancer cell proliferation and induces apoptosis by regulating the PI3K/AKT/mTOR pathway."

IO biomarker • Journal • Colorectal Cancer • Oncology • Solid Tumor • BCL2 • CASP3 • CDC37 • HSP90AA1

HSP90AB1 is a host factor that promotes Porcine deltacoronavirus replication. (PubMed, J Biol Chem) - "Infected cells treated with HSP90 inhibitors 17-AAG and VER-82576 also showed a significantly suppressed PDCoV infection, although KW-2478, which does not affect the ATPase activity of HSP90AB1, had no effect on PDCoV infection...Further studies showed that HSP90AB1 protects N protein from degradation via the proteasome pathway. In summary, our results reveal a key role for HSP90AB1 in the mechanism of PDCoV infection and contribute to provide new host targets for PDCoV antiviral research."

Journal • Preclinical • Infectious Disease • Novel Coronavirus Disease • HSP90AB1 • KEAP1

HSP90AB1 Is a Host Factor Required for Transmissible Gastroenteritis Virus Infection. (PubMed, Int J Mol Sci) - "The results showed that the knockdown of HSP90AB1 and HSP90 inhibitor VER-82576 treatment resulted in a reduction in TGEV M gene mRNA levels, the N protein level, and virus titers in a dose-dependent manner, while the knockdown of HSP90AA1 and KW-2478 treatment had no significant effect on TGEV infection...Moreover, the TGEV-induced upregulation of proinflammatory cytokine (IL-6, IL-12, TNF-α, CXCL10, and CXCL11) expression was significantly inhibited by VER-82576. In summary, these findings indicated that HSP90AB1 is a host factor enhancing TGEV infection, and the HSP90 inhibitor VER-82576 could reduce TGEV infection and proinflammatory cytokine production, providing a new perspective for TGEV antiviral drug target design."

Journal • Gastroenterology • Gastrointestinal Disorder • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases • CXCL10 • CXCL11 • HSP90AB1 • IL12A • IL6 • TNFA

A Drug Screening Reveals Minocycline Hydrochloride as a Therapeutic Option to Prevent Breast Cancer Cells Extravasation across the Blood-Brain Barrier. (PubMed, Biomedicines) - "KW-2478, buparlisib, and minocycline hydrochloride (MH) promoted maximal expression of the junctional protein β-catenin and induced 4T1 cells nucleus changes...MH was the most promising in preventing 4T1 migration and BBB disruption, tumour and endothelial cytoskeleton-associated proteins modifications, and miRNA deregulation. Our data revealed MH's ability to improve BBB properties, while compromising BCCs viability and interaction with BBB endothelial cells, besides restoring miRNAs' homeostasis, paving the way for MH repurposing for BCBM prevention."

Journal • Breast Cancer • Oncology • Solid Tumor • HSP90AA1

The HSP90 inhibitor KW-2478 depletes the malignancy of BCR/ABL and overcomes the imatinib-resistance caused by BCR/ABL amplification. (PubMed, Exp Hematol Oncol) - "This finding demonstrated that KW-2478 had anticancer properties in imatinib-sensitive and imatinib-resistant CML cells and illustrated the possible mechanisms. This study provides an alternative choice for CML treatment, especially for TKI-resistant patients with BCR/ABL amplification and TKI-intolerant patients."

Journal • Chronic Myeloid Leukemia • Hematological Malignancies • Leukemia • Oncology • CCNB1 • CDKN1A • HSP90AA1

HSP90 inhibitors 17-AAG and VER-82576 inhibit porcine deltacoronavirus replication in vitro. (PubMed, Vet Microbiol) - "HSP90 inhibitors have potent inhibitory effects against the replication of numerous viruses, hence we evaluated three HSP90 inhibitors, 17-AAG, VER-82576, and KW-2478, for their effects on PDCoV infection in vitro...We found that both 17-AAG and VER-82576 inhibited the expressions of TNF-α, IL-6, and IL-12 to varying degrees, but in a dose dependent manner. From our data we can conclude that the HSP90 inhibitors 17-AAG and VER-82576 are promising candidates for the treatment of PDCoV infection."

Journal • Preclinical • Infectious Disease • Novel Coronavirus Disease • IL12A • IL6 • KEAP1 • TNFA

Anti-NSCLC activity in vitro of Hsp90 inhibitor KW-2478 and complex crystal structure determination of Hsp90-KW-2478. (PubMed, J Struct Biol) - "Among them, twenty-two derivatives exhibited increased binding force with Hsp90 evaluated by molecular docking assay. The results would provide new guidance for anti-NSCLC new drug development based on the lead compound KW-2478."

Journal • Preclinical • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • HSP90AA1

Inhibition of HSP90 overcomes melphalan resistance through downregulation of Src in multiple myeloma cells. (PubMed, Clin Exp Med) - "We found that expression of HSP90 was higher in melphalan-resistant MM cells than in parent cells and that HSP90 inhibitors KW-2478 and NUV-AUY922 restored drug sensitivity to the level observed in parent cells. We demonstrated that treatment with KW-2478 decreased expression of Src, a client of HSP90, and suppressed the activity of ERK, Akt, and NF-κB. Our findings indicate that inhibition of HSP90 results in suppression of Src and its downstream effectors, including ERK, Akt, and NF-κB, and therefore that HSP90 inhibitors could be useful for treatment of MDR MM."

Journal • Hematological Malignancies • Multiple Myeloma • Oncology

Effect of the Hsp90 Inhibitor KW-2478 on HepG2 Cells. (PubMed, Anticancer Agents Med Chem) - "KW-2478 inhibited the proliferation of HepG2 cells, induced apoptosis and cell cycle arrest, inhibited invasion, and promoted senescence. KW-2478 affected the expression of related factors in the mitochondrial apoptotic signaling and cell cycle-related regulatory pathways. KW-2478 downregulated the expression of STAT3, which is a key factor in the JAK-STAT pathway, indicating that KW-2478 may affect the function of HepG2 cells by downregulating STAT3."

Journal • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Oncology • Solid Tumor

A High-Throughput Screen of a Library of Therapeutics Identifies Cytotoxic Substrates of P-glycoprotein. (PubMed, Mol Pharmacol) - "We used the CellTiter-Glo viability assay to test library compounds against parental KB-3-1 human cervical adenocarcinoma cells and the colchicine-selected subline KB-8-5-11 that overexpresses P-gp...ABCG2 was also found to confer high levels of resistance to AT9283, GSK-690693, and gedatolisib, whereas ispinesib, AT7519, and KW-2478 were weaker substrates...Of the 10,804 compounds screened, a total of 90 substrates were identified of which 55 were novel. P-gp expression may adversely affect the oral bioavailability or brain penetration of these compounds."

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