NVP-TAE226 / Novartis - LARVOL DELTA

Discovery of a macrocyclic FAK inhibitor GZD-257 for treatment of glioblastoma. (PubMed, Bioorg Med Chem Lett) - "Herein, TAE-226, the earliest FAK inhibitor to enter clinical trials, was used as the lead compound, and a macrocyclization-based structural optimization strategy was adopted to develop novel FAK inhibitors...Finally, flow cytometry studies indicated that GZD-257 could significantly induce apoptosis of U118-MG cells and arrest the cell cycle at the G2/M phase. Molecular docking studies suggested that GZD-257 was a highly promising ATP-competitive FAK inhibitor."

Journal • Brain Cancer • Glioblastoma • Oncology • Solid Tumor

Molecular Subtypes and Biomarkers of Ulcerative Colitis Revealed by Sphingolipid Metabolism-Related Genes: Insights from Machine Learning and Molecular Dynamics. (PubMed, Curr Issues Mol Biol) - "Notably, mebendazole and NVP-TAE226 emerged as promising therapeutic agents for UC. In conclusion, SMGs are integral to UC molecular subtyping and immune microenvironment modulation, presenting a novel framework for precision diagnosis and targeted treatment of UC."

Biomarker • Journal • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease • Metabolic Disorders • Ulcerative Colitis • FOXA2

Molecular hybridization-driven FAK inhibitors: N-2,4-diarylaminopyrimidine-3-sulfamoyl-benzamide derivatives with improved antitumor potency. (PubMed, Eur J Med Chem) - "In vivo, 10c showed good oral bioavailability and significantly inhibited HCT116 xenograft tumor growth (TGI = 62.22 % at 50 mg/kg), outperforming TAE226 (50.98 %) without inducing weight loss or hepatorenal toxicity. These results highlight 10c as a promising FAK-targeted candidate worthy of further preclinical investigation."

Journal • Oncology • PTK2

Inhibition of focal adhesion kinase enhances antitumor response of immune checkpoint inhibitor therapy in laryngeal cancer (AACR 2025) - "To investigate the significance of adhesion-dependent signaling, we used two human laryngeal cancer cell lines resistant to cisplatin: SCC17a and SQ20B. Our study is the first to show synergism of FAKi and ICI in platinum-resistant LSCC in vitro and in a syngeneic HPV-negative HNSCC mouse model in vivo. This represents an important rationale for the translation of this therapeutic combination in platinum-resistant LSCC."

Checkpoint inhibition • IO biomarker • Head and Neck Cancer • Laryngeal Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • CD4

Design, synthesis and biological evaluation of coumarin-containing 2,4-diphenylpyrimidine derivatives as novel focal adhesion kinase inhibitors for treatment of non-small cell lung cancer. (PubMed, Bioorg Med Chem Lett) - "Moreover, 8a was relatively safe to mice and inhibited the growth of implanted NSCLC tumors more potently than TAE226 in mice. Therefore, 8a may be a promising candidate for the treatment of NSCLC."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • MMP2 • MMP9

Discovery of 2,4-diaminopyrimidine derivatives as potent inhibitors of FAK capable of activating the Hippo pathway for the treatment of esophageal squamous cell carcinoma. (PubMed, Eur J Med Chem) - "Extensive structure-activity relationship studies were conducted based on the lead FAK inhibitor TAE-226 to enhance the inhibitory potency, and the most potent compound 8b (MY-1576) as a FAK inhibitor ultimately was identified...MY-1576 also effectively suppressed the tumor growth in the KYSE30 xenograft mouse models with good safety profiles, and potently down-regulated the autophosphorylation of FAK and the levels of YAP/TAZ in vivo. Taken together, these results indicate that MY-1576, functioning as a FAK inhibitor capable of activating the Hippo pathway, is a promising candidate against ESCC."

Journal • Esophageal Cancer • Esophageal Squamous Cell Carcinoma • Oncology • Squamous Cell Carcinoma

Generation of BT-Amide, a Bone-Targeted Pyk2 Inhibitor, Effective via Oral Administration, for the Prevention of Glucocorticoid-Induced Bone Loss. (PubMed, J Med Chem) - "We synthesized BT-Amide by linking a derivative of TAE-226, a Pyk2 inhibitor, with alendronic acid. Oral administration (gavage) of BT-Amide prevented GC-induced bone loss in mice without causing skin lesions, or elevation of any organ toxicity markers. These findings introduce BT-Amide as the first orally effective bone-targeted Pyk2 inhibitor for preventing GC-induced bone loss while minimizing off-target effects."

Journal • Osteoporosis • Rheumatology • TYK2

Focal adhesion kinase and its epigenetic interactors as diagnostic and therapeutic hints for pediatric hepatoblastoma. (PubMed, Front Oncol) - "Finally, TAE226 caused a significant reduction of pTyr397FAK, epigenetic regulators, AFP, EPCAM, OCT4, and SOX2, in association with anti-proliferative and pro-apoptotic effects on HB cells. Our results suggest a role of FAK in HB that requires further investigations mainly focused on the exploration of its effective diagnostic and therapeutic translatability."

Journal • Gastrointestinal Cancer • Hepatoblastoma • Hepatocellular Cancer • Hepatology • Oncology • Pediatrics • Solid Tumor • AFP • POU5F1 • SOX2

circMTO1/miR-30c-5p/SOCS3 axis alleviates oral submucous fibrosis through inhibiting fibroblast-myofibroblast transition. (PubMed, J Oral Pathol Med) - "circMTO1/miR-30c-5p/SOCS3 axis regulates FMT in arecoline-treated BMFs via the FAK/PI3K/AKT pathway. Expanding the sample size and in vivo validation could further elucidate their potential as therapeutic targets for OSF."

Journal • Fibrosis • Immunology • MicroRNA 30c • MTO1 • SOCS3 • VIM

Discovery of 2,4-diarylaminopyrimidine derivatives bearing sulfonamide moiety as novel FAK inhibitors. (PubMed, Bioorg Chem) - "Furthermore, these three compounds displayed higher selectivity of cancer cells over normal cells (SI value > 14), compared to the positive control TAE226 (SI value = 1.63)...Additionally, compound 7b, which display the best anti-FAK potency, can inhibit the clone formation and migration of HCT-116 cells, and cause cell cycle arrest at G2/M phase, inducing apoptosis by promoting ROS production. Overall, these results suggest that 7b is a valuable FAK inhibitor that deserves further optimization to improve its druggability."

Journal • Oncology

Stearic acid promotes lipid synthesis through CD36/Fyn/FAK/mTORC1 axis in bovine mammary epithelial cells. (PubMed, Int J Biol Macromol) - "Inhibition of FAK/mTORC1 by TAE226/Rapamycin attenuated SA-induced TAG synthesis, inactivated FAK/mTORC1 signaling, and downregulated the lipogenic genes PPARG, CD36, ACSL1, SCD, GPAT4, LIPIN1, and DGAT1 at the mRNA and protein levels in BMECs. Thus, stearic acid promotes lipogenesis through CD36 and Fyn/FAK/mTORC1 signaling in BMECs. Our findings provide novel insights into the underlying molecular mechanisms by which LCFA supplements promote lipid synthesis in BMECs."

Journal • ACSL1 • CD36 • LPIN1 • LYN • PPARG • TSC2

Design, synthesis, and biological evaluation of diaminopyrimidine derivatives as novel focal adhesion kinase inhibitors. (PubMed, RSC Med Chem) - "Herein, 24 diaminopyrimidine derivatives were designed and synthesized based on TAE-226...Compound A12 was also selected for molecular docking studies and the prediction of molecular properties and drug-like properties. These results indicated that compound A12 could be used as a potential lead compound targeting FAK for further development."

Journal • Oncology • PTK2

Design, synthesis and biological evaluation of novel 2,4-diaminopyrimidine cinnamyl derivatives as inhibitors of FAK with potent anti-gastric cancer activities. (PubMed, Bioorg Chem) - "In this study, twenty-one novel 2,4-diaminopyrimidine cinnamyl derivatives as inhibitors targeting FAK were designed and synthesized based on the structure of TAE-226, and the inhibitory effects of these compounds on both the FAK enzyme and three cancer cell lines (MGC-803, HCT-116, and KYSE30) were investigated...In addition, compound 12s also efficiently inhibited the proliferation, induced apoptosis and cellular senescence in MGC-803 cells. In conclusion, compound 12s emerges a potent FAK inhibitor that could exert potent inhibitory activity against gastric cancer cells."

Journal • Gastric Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

Pyk2 regulates sepsis-induced lung injury via ferroptosis. (PubMed, Iran J Basic Med Sci) - "Experimental mouse models revealed that treatment with Pyk2 inhibitor TAE226 can significantly alleviate lung injury, downregulate pro-inflammatory responses and decrease markers of ferroptosis, which were induced by LPS...Further, we found a negative correlation between serum Pyk2 and Fe levels, which was consistent with the mechanism identified in the mouse model. Pyk2 inhibitor of ferroptosis is a promising therapeutic candidate against sepsis-related ALI."

Journal • Acute Lung Injury • Infectious Disease • Inflammation • Respiratory Diseases • Septic Shock

Design, synthesis and biological evaluation of 4-arylamino-pyrimidine derivatives as focal adhesion kinase inhibitors. (PubMed, Bioorg Chem) - "Especially, compounds 8d and 9b revealed the highest activity with IC values of 0.975 μM and 1.033 μM, which was much potent than the positive control TAE-226 (IC = 2.659 μM)...Molecular docking and molecular dynamics simulation investigations suggested that compounds 8d and 9b could firmly occupy the ATP binding site of FAK. These findings supported the further researches of compounds 8d and 9b as FAK inhibitors for antitumor drug discovery."

Journal • Oncology

PTK2B regulates immune responses of neutrophils and protects mucosal inflammation in ulcerative colitis. (PubMed, FASEB J) - "As expected, UC patients treated with infliximab, an anti-TNF-α agent, showed significantly reduced level of PTK2B in neutrophils, as well as in the intestinal mucosa. Additionally, mice treated with TAE226 exhibited the same effects. In conclusion, PTK2B is involved in the pathogenesis of UC by promoting the migration of neutrophils and inhibiting mucosal inflammation, highlighting PTK2B as a new potential therapeutic target to treat UC."

Journal • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease • Mucositis • Oncology • Ulcerative Colitis • CXCR2 • MPO • PTK2B • S100A8 • S100A9 • TYK2

PYK2 regulates PD-L1 expression via JAK/STAT signaling in melanoma (ISID 2023) - "VS6063 and TAE226 were used as Proline-rich tyrosine kinase 2 (PYK2) inhibitors. Our results showed that PYK2 inhibitors decreased the mRNA transcription and protein expression of PD-L1, and then strengthen the anti-tumor immunity. Our results showed that PYK2 inhibitors might be a novel candidate medicines when combined to immune checkpoint inhibitors in melanoma."

IO biomarker • Brain Cancer • CNS Tumor • Glioblastoma • Immune Modulation • Melanoma • Oncology • Solid Tumor • IFNG • IRF1 • STAT1 • TYK2

FERMT1 Is a Prognostic Marker Involved in Immune Infiltration of Pancreatic Adenocarcinoma Correlating with mA Modification and Necroptosis. (PubMed, Genes (Basel)) - "Finally, FERMT1 overexpression may be sensitive to chemotherapy drugs such as Palbociclib, AM-5992 and TAE-226. FERMT1 can serve as a diagnostic and prognostic marker of PAAD, which is connected with immune cell infiltration and the modulation of mA and necroptosis."

Biomarker • Journal • Gastrointestinal Cancer • Hepatology • Immune Modulation • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor • FERMT1

Design, synthesis and evaluation of nitric oxide releasing derivatives of 2,4-diaminopyrimidine as novel FAK inhibitors for intervention of metastatic triple-negative breast cancer. (PubMed, Eur J Med Chem) - "The most active compound 8f not only significantly inhibited FAK kinase activity (IC = 27.44 nM), displayed potent inhibitory effects on the proliferation (IC = 0.126 μM), invasion and migration of MDA-MB-231 cells, superior to the most widely studied FAK inhibitor, TAE226, bearing 2,4-diaminopyrimidine, but also released high levels of NO, contributing to blockage of FAK mediated-signaling pathways by upregulating of p53 as well as suppressing the Y397 phosphorylation and its downstream effectors, including p-Akt, MMP-2, and MMP-9 via kinase-independent manner, leading to apoptosis induction and decrease of FAs and SFs in TNBC cells. Importantly, 8f inhibited the lung metastasis of TNBC in vivo. Together, 8f may serve as a promising candidate for the treatment of metastatic TNBC."

Journal • Metastases • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • MMP2 • MMP9

The dual FAK-HDAC inhibitor MY-1259 displays potent activities in gastric cancers in vitro and in vivo. (PubMed, Bioorg Chem) - "MY-1259 exhibited more effective antitumor effect in vivo than the HDAC inhibitor SAHA and FAK inhibitor TAE-226 alone or in combination, showing the advantages of FAK/HDAC dual inhibitors in the treatment of gastric cancers. Therefore, the results in this work suggested that inhibition of FAK and HDAC by MY-1259 might represent a promising strategy for the treatment of gastric cancers."

Journal • Preclinical • Gastric Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • HDAC1 • HDAC2 • HDAC3

Rho-associated kinase1 promotes laryngeal squamous cell carcinoma tumorigenesis and progression via the FAK signaling pathway. (PubMed, Discov Oncol) - "Inhibiting FAK activity with TAE226 observably impairs the tumor-promoting effects. In conclusion, ROCK1 promotes LSCC tumorigenesis and progression via the FAK signaling pathway, targeting the ROCK1 molecule may represent potential targets for clinical LSCC treatment."

Journal • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • ROCK1

Identification of novel and potent PROTACs targeting FAK for non-small cell lung cancer: Design, synthesis, and biological study. (PubMed, Eur J Med Chem) - "Additionally, the in vitro preliminary drug-like properties evaluation of PROTAC B5 showed outstanding plasma stability and moderate membrane permeability. Together, current results provided a promising FAK PROTAC B5 as lead compound for cancer-related drug discovery and FAK-degradation functions exploration in biological systems."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Targeted Protein Degradation

Design, synthesis and biological evaluation of novel FAK inhibitors with better selectivity over IR than TAE226. (PubMed, Bioorg Chem) - "Moreover, 18b showed adequate oral bioavailability of 16.37% and 75.90% tumor growth inhibition in the HCT116 xenograft model was observed. These results indicate that 18b is a promising selective inhibitor of FAK."

Journal • Oncology • IR

Focal adhesion kinase inhibitor TAE226 combined with Sorafenib slows down hepatocellular carcinoma by multiple epigenetic effects. (PubMed, J Exp Clin Cancer Res) - "Altogether, our findings provide the first evidence that TAE226 combined with SOR efficiently reduces HCC growth in vitro and in vivo. Also, our data highlight that deep analysis of FAK nuclear interactome may lead to the identification of new promising targets for HCC therapy."

Journal • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor • HDAC1

Design, Synthesis, and Biological Evaluation of Novel Covalent Inhibitors Targeting Focal Adhesion Kinase. (PubMed, Bioorg Med Chem Lett) - "Forty-one new focal adhesion kinase (FAK) covalent inhibitors were designed and synthesized based on FAK inhibitor TAE226...A 74.20% inhibition of tumor growth in the HCT116 xenograft model was also observed. These data indicate that 11w is a promising covalent inhibitor of FAK."

Journal • Oncology