ALW-II-41-27 / University of Naples Federico II - LARVOL DELTA

Novel tyrosine kinase/MEK inhibitor combinations impair the viability and invasive potential of TNBC cell lines (AACR 2025) - "We identified several cytokines secreted in response to the pan-Raf inhibitor CCT196969, the MEK inhibitor (MEKi) trametinib and the ERK inhibitor (ERKi) ulixertinib such as FGF-basic, FGF-19, MIF and angiogenin. Lastly, the trametinib/ALW-II-41-27 combination revealed a significant reduction in cell migration and invasion compared to trametinib treatment alone. These findings indicate that ponatinib and ALW-II-41-27 combined with MAPKi could be a promising novel therapeutic approach for TNBC."

Preclinical • Oncology • Triple Negative Breast Cancer • ALK • ERBB3 • FGF19 • FGFR1 • FGFR3 • HER-2

The impact of EphA2 in the malignancy of CIC-DUX sarcomas (AACR 2025) - "Therefore, we have successfully tested the efficacy of a combination between ALW-II-41-27, a widely used inhibitor of EphA2 kinase activity, and IGF-1R/AKT inhibitors in preclinical models...Scotlandi. For HaloPROTAC studies support was provided by the Italian Ministry of Health through the Executive Programme of Cooperation in the field of Science and Technology between Italy and the USA 2023-2025, MAECI-2023-23683465, to C. Mancarella."

Ewing Sarcoma • Oncology • Sarcoma • Solid Tumor • IGF2

Neuronal guanine nucleotide exchange factor promotes the axonal growth and cancer cell proliferation via Ephrin-A3/EphA2 axis in lung adenocarcinoma. (PubMed, J Transl Med) - "NGEF facilitates the infiltration of nerve and the growth of cancer cells in lung adenocarcinoma through the Ephrin-A3/EphA2 pathway, suggesting that NGEF is a promising target for disrupting interactions between nerves and tumors. Biomaterials that focus on NGEF are anticipated to be a potential treatment option for lung cancer."

Journal • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EFNA3 • KIF4A • NGEF • PABPC1

A multi-model approach identifies ALW-II-41-27 as a promising therapy for osteoarthritis-associated inflammation and endochondral ossification. (PubMed, Heliyon) - "Additionally, systemic subcutaneous administration of ALW-II-41-27 in a mouse osteoarthritic model attenuated joint degeneration by reducing local inflammation and pathological endochondral ossification. Collectively, this study demonstrates a novel drug discovery pipeline that integrates computational, experimental, and animal models, paving the way for the development of disease-modifying treatments for osteoarthritis."

Journal • Developmental Disorders • Immunology • Inflammation • Oncology • Osteoarthritis • Pain • Rheumatology

EphA2 blockage ALW-II-41-27 alleviates atherosclerosis by remodeling gut microbiota to regulate bile acid metabolism. (PubMed, NPJ Biofilms Microbiomes) - "In clinical, lower plasma DCA and HDCA levels were determined in CAD patients using quantitative metabolomics and exhibited a negative correlation with higher monocytes EphA2 expression. Our findings underscore the potential of ALW-II-41-27 as a novel therapeutic agent for atherosclerosis, highlighting its capacity to modulate gut microbiota composition and bile acid metabolism, thereby offering a promising avenue for CAD."

Journal • Atherosclerosis • Cardiovascular • Coronary Artery Disease • Dyslipidemia • Gastrointestinal Disorder • Inflammation • Metabolic Disorders • Transplantation • APOE • EPHA2

Preclinical and Toxicology Assessment of ALW-II-41-27, an Inhibitor of the Eph Receptor A2 (EphA2). (PubMed, Drugs R D) - "In our initial general safety and toxicology assessments, ALW-II-41-27 displayed no inherent safety concerns in the analyzed parameters. These data support broader in vivo testing of the inhibitor as a timed adjunct therapy to the deleterious proinflammatory host immune response often associated with anti-Pneumocystis therapy."

Journal • Preclinical • Infectious Disease • Inflammation • Pneumonia • Respiratory Diseases • EPHA2 • IL1B

Comprehensive analysis of EphA2 in pan-cancer: A prognostic biomarker associated with cancer immunity. (PubMed, Clin Exp Pharmacol Physiol) - "Our first pan-cancer study of EphA2 provides insight into the prognostic and immunological roles of EphA2 in different tumours, suggesting that EphA2 might be a potential biomarker for poor prognosis and immune infiltration in cancer."

Biomarker • Journal • Pan tumor • Tumor mutational burden • Brain Cancer • CNS Tumor • Glioma • Lung Cancer • Microsatellite Instability • Oncology • Solid Tumor • CD8 • EPHA2 • MSI • PD-L1 • TMB

Targeting host tyrosine kinase receptor EphA2 signaling via small-molecule ALW-II-41-27 inhibits macrophage pro-inflammatory signaling responses to Pneumocystis carinii β-glucans. (PubMed, Antimicrob Agents Chemother) - "In vitro, when ALW-II-41-27 is administrated via intraperitoneal to mice prior to the administration of highly proinflammatory Saccharomyces cerevisiae β-glucans in the lung, a significant reduction in TNF-alpha release was noted in the ALW-II-41-27 pre-treated group. Taken together, our data suggest that targeting host lung macrophage activation via EphA2 receptor-fungal β-glucans interactions with ALW-II-41-27 or other EphA2 receptor kinase targeting inhibitors might be an attractive and viable strategy to reduce detrimental lung inflammation associated with PJP."

Journal • Infectious Disease • Inflammation • Pneumonia • Respiratory Diseases • TNFA

Inhibition of EphA2 protects against atherosclerosis by synergizing with statins to mitigate macrophage inflammation. (PubMed, Biomed Pharmacother) - "Furthermore, the proinflammatory effect of atorvastatin was neutralized by an addition of recombinant Fc-ephrinA1, a selective Eph receptor tyrosine kinase inhibitor (ALW-II-41-27) or EphA2-silencing adenovirus (siEphA2). Increased plaque stability index was also observed following the addition of siEphA2, as evidenced by increased collagen and smooth muscle content and diminished lipid accumulation and macrophage infiltration. The data suggest that blockage of EphA2 provides an additional therapeutic benefit for further improving the anti-atherogenic effects of statins."

Journal • Atherosclerosis • Cardiovascular • Coronary Artery Disease • Dyslipidemia • Inflammation • APOE • EFNA1 • EPHA2 • HDAC11 • IL1B • KLF4 • NLRP3 • TNFA

EphA2 as a phase separation protein associated with ferroptosis and immune cell infiltration in colorectal cancer. (PubMed, Aging (Albany NY)) - "We also found that EphA2 can form liquid-liquid phase separation condensates on cell membrane, which can be disrupted by ALW-II-41-27, an inhibitor of EphA2. In addition, we found that EphA2 expression in colorectal cancer was positively correlated with the expression of ferroptosis-related genes and the infiltration of multiple immune cells. These findings suggest that EphA2 is a novel membrane protein with phase separation ability and is associated with ferroptosis and immune cell infiltration, which further suggests that malignant progression of colorectal cancer may be inhibited by suppressing the phase separation ability of EphA2."

Immune cell • Journal • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • EPHA2

Targeting the KLF5-EphA2 axis can restrain cancer stemness and overcome chemoresistance in basal-like breast cancer. (PubMed, Int J Biol Sci) - "Furthermore, the EphA2 inhibitor ALW-II-41-27 could effectively reduce EphA2 pS897 and tumor cell stemness in vitro and significantly enhance the sensitivity of xenografts to the chemotherapeutic drugs PTX and DDP in vivo. Clinically, tumor samples from breast patients with less response to neoadjuvant chemotherapy showed a high level of EphA2 pS897 expression. In conclusion, KLF5-EphA2 promotes stemness and drug resistance in BLBC and could be a potential target for the treatment of BLBC."

Journal • Breast Cancer • Oncology • Solid Tumor • KLF5 • TNFA

Targeting Host Tyrosine Kinase Receptor EPHA2 Signaling Affects Uropathogen Infection in Human Bladder Epithelial Cells. (PubMed, Pathogens) - "The significance of EPHA2 signaling for uropathogen infection was investigated by silencing EPHA2 expression using RNA interference or by inhibiting the kinase activity of EPHA2 using small-molecule compounds such as dasatinib or ALW-II-41-27. Both preventive and therapeutic tyrosine kinase inhibition significantly reduced the intracellular bacterial load. Thus, our results demonstrate the involvement of host cell EPHA2 receptor during intracellular uropathogen infection of BECs, and targeting RTK activity is a viable non-antibiotic therapeutic strategy for managing recurrent UTIs."

Journal • Infectious Disease • Nephrology • Pneumonia • EPHA2

TYROSINE KINASE INHIBITOR ALW-II-41-27 ATTENUATES OSTEOPHYTOSIS AND SYNOVITIS IN MICE (OARSI 2022) - "Previously, we have identified an increased expression of Ephrin receptor A2 (EphA2), a tyrosine kinase associated with inflammation, in osteoarthritic cartilage and in hypertrophic cartilage of the growth plate. The aim of this study was to examine the effect of EphA2 inhibition on chondrocytes hypertrophy and inflammation in vitro and its potential to mitigate osteophytosis and synovitis in vivo."

Preclinical • Immunology • Inflammation • Osteoarthritis • Pain • Rheumatology

ALW-II-41-27, an EphA2 inhibitor, inhibits proliferation, migration and invasion of cervical cancer cells via inhibition of the RhoA/ROCK pathway. (PubMed, Oncol Lett) - "Taken together, the present findings revealed that ALW-II-41-27 inhibited CC cell proliferation, migration and invasion by blocking the RhoA/ROCK pathway. These findings provide further insight into the mechanism of CC progression and significant information for the development of potential therapeutic targets for CC."

Journal • Cervical Cancer • Oncology • Solid Tumor • EPHA2 • RHOA

EphA2 Expression in Bone Sarcomas: Bioinformatic Analyses and Preclinical Characterization in Patient-Derived Models of Osteosarcoma, Ewing's Sarcoma and Chondrosarcoma. (PubMed, Cells) - "Indeed, we observed a significant dose-dependent antitumor effect of the EphA2-inhibitor ALW-II-41-27 in patient-derived in vitro models. In conclusion, EphA2 targeting represents a promising novel therapeutic strategy against bone sarcomas."

IO biomarker • Journal • Preclinical • Ewing Sarcoma • Oncology • Osteosarcoma • Sarcoma • Solid Tumor • EPHA2

Blocking of EphA2 on Endometrial Tumor Cells Reduces Susceptibility to Vδ1 Gamma-Delta T-Cell-Mediated Killing. (PubMed, Front Immunol) - "The EphA2 blocking studies were performed using antibody, small-molecule inhibitor ALW-II-41-27, and the CRISPR/Cas9...Specifically, we found that blocking of EphA2 expression resulted in significant inhibition of endometrial tumor killing mediated by Vδ1 γδ T cells. These results suggest that EphA2 is involved in tumor cell lysis and contributes to susceptibility to Vδ1 γδ T cells cytotoxic reactivity."

Journal • Breast Cancer • Endometrial Cancer • Endometriosis • Gynecology • Immunology • Infertility • Inflammation • Oncology • Ovarian Cancer • Pain • Sexual Disorders • Solid Tumor • EPHA2

A Putative Single-Photon Emission CT Imaging Tracer for Erythropoietin-Producing Hepatocellular A2 Receptor. (PubMed, ACS Med Chem Lett) - "[I]ETB was designed on the basis of ALW-II-41-27, an inhibitor of EphA2 receptor kinase...In addition, [I]ETB uptake in tumors was visualized via SPECT/CT imaging. On the basis of the above, [I]ETB can be considered a potential SPECT imaging tracer for the EphA2 receptor."

Journal • Oncology

Quantitative Tyrosine Phosphoproteomic Analysis of Resistance to Radiotherapy in Nasopharyngeal Carcinoma Cells. (PubMed, Cancer Manag Res) - "Furthermore, an ATP-competitive EPHA2 RTK inhibitor (ALW-II-41-27, ALW) reduced EPHA2 Y772 phosphorylation and increased the expression of E-cadherin in CNE2-IR cells...In conclusion, phosphoproteomic approach allowed us to link tyrosine kinases signaling with radioresistance in NPC. Further studies are necessary to delineate the molecular function of EPHA2/E-cadherin signaling in radioresistant NPC and to explore rational combination therapy and its underlying mechanism."

Journal • Nasopharyngeal Carcinoma • Oncology • Solid Tumor • ABL1 • CDH1 • EGFR • EPHA2 • IGF1R

[VIRTUAL] TARGETING EphA2 SUPPRESSES HEPATOCELLULAR CARCINOMA INITIATION AND PROGRESSION (AASLD 2020) - "The effect of an EphA2 inhibitor ALW-II-41-27 on HCC growth was evaluated using In vitro growth assays and xenograft models... Inhibition of EphA2 suppresses HCC growth by dual inhibition of JAK1/STAT3 and AKT signaling. EphA2 is a promising therapeutic target for HCC."

Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Oncology • Solid Tumor • EPHA2 • JAK1 • MET • STAT3

Enhanced YB1/EphA2 axis signaling promotes acquired resistance to sunitinib and metastatic potential in renal cell carcinoma. (PubMed, Oncogene) - "Furthermore, pharmacological inhibition of EphA2 through the small molecule inhibitor ALW-II-41-27 reduced the proliferation of sunitinib-resistant tumor cells, suppressed tumor growth in vivo, and restored the sensitivity of sunitinib-resistant tumor cells to sunitinib in vitro and in vivo. Mechanistically, YB1 increases the protein levels of EphA2 by maintaining the protein stability of EphA2 through inhibition of the proteasomal degradation pathway. Collectively, our findings provide the theoretical rationale that ccRCC metastasis and RTK-directed therapeutic resistance could be prospectively and purposefully targeted."

Journal • Preclinical • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • Von Hippel-Lindau Syndrome • EPHA2 • EPO • VHL • YBX1

Y772 phosphorylation of EphA2 is responsible for EphA2-dependent NPC nasopharyngeal carcinoma growth by Shp2/Erk-1/2 signaling pathway. (PubMed, Cell Death Dis) - "Moreover, we observed that EphA2 tyrosine kinase inhibitor ALW-II-41-27 inhibited pY772-EphA2 and EphA2-Y772A decreased the inhibitory effect of ALW-II-41-27 on NPC cell proliferation. Collectively, our results demonstrate that pY772-EphA2 is responsible for EphA2-dependent NPC cell growth in vitro and in vivo by activating Shp2/Erk-1/2 signaling pathway, and is a pharmacologic target of ALW-II-41-27, suggesting that pY772-EphA2 can serve as a therapeutic target in NPC and perhaps in other cancers."

Journal • Nasopharyngeal Carcinoma • Oncology • Solid Tumor • EPHA2

[VIRTUAL] Investigations of drug synergy reveal promising efficacy of EphA2 inhibition combined with CDK inhibition in triple-negative breast cancer (AACR-II 2020) - "Furthermore, genetic knockdown or inhibition of EphA2 with the small molecule ALW-II-41-27 (ALW) reduces cancer cell growth in vitro and in vivo...To this end, TNBC lines MDA-MB-231, BT-549, HCC1395, and HCC1187 were seeded in 96-well plates and exposed to ALW alone or in combination with chemotherapeutic agents doxorubicin and paclitaxel, CDK inhibitor SCH-727965, and MCL-1 inhibitor S63845 and cell viability assessed by MTT assay at 48 hours...Furthermore, TUNEL assays show that addition of SCH-727965 to ALW significantly increases the induction of apoptosis by HCC1395 and HCC1187 cells. These preclinical studies demonstrate that combination of ALW and SCH-727965 potently reduces TNBC cell growth and promotes cell death, representing promising early data on the effects of EphA2 inhibition as part of a combination targeted therapeutic approach for triple-negative breast cancer."

Clinical • Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • EPHA2

EphA2 inhibition suppresses proliferation of small-cell lung cancer cells through inducing cell cycle arrest. (PubMed, Biochem Biophys Res Commun) - "Furthermore, small molecule inhibitors of EphA2 (ALW-II-41-27 and dasatinib) also exclusively inhibited proliferation of EphA2-positive SCLC cells by the same mechanism. Collectively, EphA2 could be a promising candidate as a therapeutic target for SCLC."

Journal • Lung Cancer • Neuroendocrine Tumor • Oncology • Small Cell Lung Cancer • Solid Tumor • Thoracic Cancer