An efficient CuI-catalyzed fluorodesulfurization for the synthesis of monofluoromethyl aryl ethers using DAST at room temperature has been developed. This approach exhibits a good functional group tolerance, a broad substrate scope, and a high synthesis efficiency.
Articles you may be interested inHigh-performance optoelectrical dual-mode memory based on spiropyran-containing polyimide Appl. Phys. Lett. 97, 253304 (2010); 10.1063/1.3529453Nanometer-scale data storage on 3-phenyl-1-ureidonitrile thin film using scanning tunneling microscopy
The first O-difluorodeuteromethylation of phenols using commercial diethyl bromodifluoromethylphosphonate and deuterium oxide to prepare various difluorodeuteromethyl aryl ethers is reported. This facile method affords a convenient way to introduce OCFD groups into organic molecules.
Hippo/YAP pathway plays an essential role in cell proliferation, tissue regeneration, and tumorigenesis. The emerging evidence shows that hyperactivation of the Hippo/YAP pathway induces metastasis, chemoresistance, and the attribute of cancer stem cells. Dysregulated Hippo/YAP pathway can be a dominant driver of mesothelioma, meningioma, and schwannoma. It has been reported that Hippo/YAP oncogenic activation in mesothelioma is driven by NF2 loss function. In addition, it contributes to 10% of all cancers, including lung, gastric, colon, cervical, ovarian, breast, melanoma, hepatocellular, and squamous cell carcinoma. Despite the urgent need to develop a therapeutic strategy to curb the dysregulated pathway, YAP/TAZ is difficult to be directly targeted with small molecule inhibitors because of the lack of a catalytic niche. TEADs require auto-palmitoylation to become functional. Therefore, small molecules that target palmitoylation of TEAD have been explored and VT3989 (NCT04665206) and IK-930 (NCT05228015) have success to enter the clinical trials. To target cancers with dysregulated Hippo/Yap pathway, we have discovered and are developing TY-0584, which is a potent and orally available YAP/TEAD inhibitor in the IND enabling stage. The results of PK and toxicity studies of TY-0584 showed a favorable safety profile. TY-0584 had excellent efficacy in the malignant mesothelioma H226 CDX mouse model, which is driven by NF2 deletion mutation. TY-0584 treatment also demonstrated good efficacy in the head and neck cancer PDX tumor mouse model. In previous studies, Hippo/Yap signaling promotes drug resistance to EGFR-targeted therapies in non-small cell lung cancer (NSCLC). To relax the YAP resistance mechanism in EGFR treatment, we asked if combined YAP inhibition grants an extension of responses to EGFR therapy. To this end, we treated EGFR-driven NSCLC cell models with TY-0584 and TY-9591. TY-9591 is a third-generation EGFR inhibitor developed by TYK Medicines and is currently under a pivotal Phase III clinical investigation in China (NCT05382728). The results show that the combination treatment not only offers synergistic effects, but also enhances apoptosis, compared to single drug treatment. Our in vivo data further underscores this exciting finding. Our studies showed that TY-9591 had excellent efficacy in the PC9 CDX mouse model, but tumors gradually recurred as many targeted cancer therapies did. In line with the results of the in-vitro experiments, another YAP/TEAD inhibitor TY-0536 in combination with TY-9591 significantly delay the tumor regrowth in the PC9 CDX mouse model. In summary, we identified a potent and orally available YAP/TEAD inhibitor TY-0584 which is a promising candidate for further clinical validation. [Shengli Dong and Apeng Liang contributed equally to this work. Jun Li, Shengli Dong, and Apeng Liang are the corresponding authors.] Citation Format: Apeng Liang, Shengli Dong, Guangbin Liu, Zhengfei Guo, Meihua Li, Shuaibo Han, Yundi Cao, Yian Tu, Chao Zhou, Yu Yu, Linglin Xiao, Wei Huang, Xinlong Yang, Lian Fang, Haoyun Li, Chengshan Niu, Mingyu Jiang, Feng Xing, Shaoqing Chen, Jun Li, Yusheng Wu. TY-0584: A potent, orally available small molecule YAP/TEAD inhibitor, exhibits anti-tumor effects in vitro and in vivo. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4491.
Epidermal growth factor receptor (EGFR) activating mutations represent major drivers to the development of non-small cell lung cancer (NSCLC). Among the oncogenic EGFR mutations, a significant cohort, counting for approximately 4-10% of the EGFR mutation spectrum, bear EGFR exon 20ins mutations. Meanwhile, approximately 2% of NSCLC patients bear hotspot mutations in HER2. Strikingly, over 90% of the HER2 mutations occurred in NSCLC are identified as exon 20ins mutations. Despite the successful launch of 1st, 2nd, and 3rd generation of EGFR inhibitory agents in the clinic that inactivate oncogenic EGFR signaling through targeting specific EGFR mutations, de novo or acquired, none of these standard-of-care therapies is specific to EGFR exon 20ins or HER2 exon 20ins. In addition, trastuzumab and EGFR-TKIs have limited effectiveness for NSCLC patients with HER2 exon 20ins mutation. TAK-788 (mobocertinib) and JNJ6372 (amivantamab-vmjw) are the FDA approvals for NSCLC driven by EGFR exon 20ins mutations. Only T-Dxd is used as a second-line treatment for NSCLC patients with HER2 mutation. Considering the large population of lung cancer and the fact that many patients are missed in diagnosis due to the heterogeneous characteristics of EGFR and Her2 exon 20ins, there are probably more than ten thousand lung cancer patients suffering the EGFR or Her2 exon 20ins mutations. There are urgent unmet medical needs to develop target therapeutics for EGFR and Her2 exon 20ins mutations. We discovered and developed TY-4028, which is a novel, potent, and orally available inhibitor targeting EGFR and Her2 exon 20ins mutations and is currently in the IND enabling stage. In EGFR-related tumor cells and genetically engineered Ba/F3 cell lines, TY-4028 showed similar or better antitumor effects than TAK-788, and better antitumor effects than DZD9008. The B/P ratio (brain tissue AUC0-last/plasma AUC0-last) of SD rats was 1.63 and 1.04 respectively after oral administration of TY-4028 in male and female SD rats, which suggested that TY-4028 had good potential to cross Blood Brain Barrier (BBB). Preclinical studies showed a good PK profile and manageable toxicity with TY-4028. TY-4028 has remarkable efficacy in mouse models of EGFR exon 20ins and HER2 exon 20ins. The data showed that all doses of TY-4028 had significant effects, and the tumors nearly demonstrated complete regression in the PDX LU0387 model and PC9 CDX model. At the same dose, the efficacy of TY-4028 was similar to that of TAK-788, while the tolerance of TY-4028 was better than that of TAK-788. At the same dose, the efficacy of TY-4028 was better than that of DZD9008. Taken together, the data demonstrated TY-4028 has great potential to meet the unmet medical needs for NSCLC patients with EGFR exon 20ins mutation or HER2 exon 20ins mutation. #Jun Li and Chengshan Niu contributed equally to this work. *They are the correspondent authors. Citation Format: Jun Li, Chengshan Niu, Zhongwei Guo, Huan Wang, Bailu Zheng, Yuge Dou, Apeng Liang, Kaige Ji, Shengli Dong, Meihua Li, Yanchao Zhao, Yazhen Zhang, Aishen Gong, Hao Liu, Xinmiao Hu, Hui Su, Mingyu Jiang, Shaoqing Chen, Xiugui Chen, Yusheng Wu. TY-4028: a novel, targeted therapy for non small-cell lung cancer with EGFR exon 20 or HER2 exon 20 insertion mutations. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4488.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.