PROTACs for Non-small Cell Lung Cancer
BOC Sciences stands at the forefront of the CRO field, and with its comprehensive PROTAC technology system, empowers global customers and accelerates the journey of new drug creation. With our cutting-edge platform and deep knowledge, we have created PROTAC molecules specifically for non-small cell lung cancer (NSCLC) therapy, opening a new chapter in personalized solutions.
Overview of non-small cell lung cancer
Lung cancer is the world's highest incidence and mortality of malignant tumors, the annual death toll can reach 1.4 million to 1.6 million, accounting for 18% of all malignant tumor deaths, with a high incidence of disease, high mortality characteristics. Depending on the type of disease, lung cancer can be classified as small cell lung cancer (SCLC) or NSCLC. NSCLC accounts for 85% of all lung cancer cases, including adenocarcinoma, squamous cell carcinoma and large cell carcinoma. More than 50% of lung cancer patients are diagnosed with advanced lung cancer, and there is no cure for patients with advanced non-small cell lung cancer, making lung cancer the most harmful type of cancer worldwide. For the past few decades, chemotherapy has been the primary treatment option for patients with advanced non-small cell lung cancer, but the treatment has limited efficacy and large side effects.
Protein degradation targeting chimeras (PROTACs) degrade target proteins by utilizing the ubiquitin proteasome pathway, subverting the concept of traditional small molecule inhibitors. Among the common mutant targets of NSCLC, PROTAC technology has successfully achieved effective degradation of proteins of the kirsten rat sarcoma viral oncogene homolog (KRAS) epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) in preclinical studies. With its unique event-driven advantages, PROTAC drugs are expected to overcome the problem of acquired drug resistance caused by small molecule inhibitors, and show good therapeutic potential for difficult drug targets, which is expected to become a new strategy for the treatment of NSCLC.
PROTAC for NSCLC therapy
EGFR PROTACs
Over the past few decades, researchers have developed four generations of EGFR inhibitors. Despite great therapeutic success, the clinical use of these EGFR inhibitors inevitably leads to acquired resistance, and PROTACs, which degrade the entire EGFR protein, may solve the resistance problem.
In 2018, Crews team for the first time used PROTAC technology to conduct protein degradation studies on EGFR receptor tyrosine kinase, verifying the feasibility of using PROTAC technology to target EGFR degradation. After ubiquitination of the target protein, PROTAC molecule can bind to play a role in the cycle, and has catalytic properties, which is expected to reduce the number of administration times compared with small molecule inhibitors. In targeted EGFR degradation studies, several research teams have also confirmed this advantage of PROTAC. In 2021, Jiang et al found in their study that PROTAC molecules can continue to degrade L858R/T790M mutant EGFR within 72 h after stopping administration at the cellular level.
Hesco's self-developed oral EGFR-PROTAC HSK40118 is currently in Phase 1 clinical treatment for advanced NSCLC with EGFR mutations. Preclinical studies have shown that HSK40118 has good inhibition and degradation activity of mutant EGFR protein in vitro, and shows excellent selectivity to wild-type EGFR. It has a significant inhibitory effect on the growth of EGFR L858R-T790M double mutation and ex19del(or L858R)-T790M-C797S triple mutation in vivo transplanted tumors, suggesting that HSK40118 will have a significant effect on patients with acquired drug resistance mutations induced by EGFR TKI. It is expected to delay or even overcome EGFR resistance mutations caused by long-term use of EGFR TKI, which has important clinical and social significance.
Inspired by small molecule dual inhibitors, in 2021, Li team designed and synthesized dual PROTAC molecules that can simultaneously target the degradation of EGFR and PARP proteins, which also opened up a new research direction for PROTAC technology.
Novel star shape dual PROTACs and dual-targeting degradation. (Zheng, M., 2021)
ALK-PROTAC
In 2018, Gray's team reported the first PROTAC molecule that can target ALK degradation, opening a new chapter in the field of ALK protein degradation. It was found that in addition to degrading ALK protein, this molecule also had A certain ability to degrade other target proteins such as PTK2, FER, RPS6KA1 and Aurora A, but its ability to degrade EML4-ALK expressing L1196M, C1156Y and G1202R resistance mutations still needed to be improved. The selection of suitable ALK ligands to improve the selectivity of ALK protein and the degradation effect of drug resistant mutations is the direction of future ALK-PROTAC research.
KRAS-PROTAC
In 2019, Arvinas reported on the patent for KRAS G12C PROTAC. They designed a large number of KRAS G12C reducers based on ARS-1620 derivatives and different E3 ligand ligands, such as compounds 44 and 45, that showed degradation activity in human NSCLC cells. More and more PROTACs for KRAS G12C have been reported, but most of them are preclinical.
The representative PROTACs targeting KRASG12C. (He, M., 2022)
On May 22, 2023, the CDE official website showed that ASP3082 developed by Astellas was declared clinical in China, which is a new drug with high efficiency and selectivity for KRAS G12D PROTAC in the world. A Phase 1 clinical trial is currently underway in previously treated patients with locally advanced or metastatic solid tumors with the KRAS G12D mutation (NCT05382559).
Our services
As a leading CRO, BOC Sciences is committed to ushering in a new era in the treatment of NSCLC. We are focused on the design, discovery and synthesis of highly effective PROTACs to revolutionize solutions for NSCLC. Our carefully constructed PROTAC platform not only gathers the industry's top scientific research wisdom, but also provides unprecedented perspectives and strategies for NSCLC treatment. Includes:
Our core competence
- We are fully committed to the treatment of non-small cell lung cancer, forge ahead, and refine PROTAC technology, aiming to create a new chapter in cancer therapy.
- Relying on our comprehensive and advanced PROTAC platform, our scientific team, a group of knowledgeable and experienced experts, is constantly exploring and striving for breakthroughs.
- We are committed to providing detailed data analysis, delivering results that are not only highly reliable, but also highly reproducible, to provide a solid foundation for your research.
- Provide seamless one-stop service, coupled with a highly competitive pricing strategy, so that you can get the maximum return on every minute of investment.
References:
- Burslem, G. M., et al. The advantages of targeted protein degradation over inhibition: an RTK case study. Cell Chemical Biology. 2018, 25(1): 67-77.
- Qu, X., et al. Effective degradation of EGFRL858R+ T790M mutant proteins by CRBN-based PROTACs through both proteosome and autophagy/lysosome degradation systems. European Journal of Medicinal Chemistry. 2021, 218: 113328.
- Zheng, M., et al. Rational design and synthesis of novel dual PROTACs for simultaneous degradation of EGFR and PARP. Journal of Medicinal Chemistry. 2021, 64(11): 7839-7852.
- He, M., et al. PROTACs: great opportunities for academia and industry (an update from 2020 to 2021). Signal Transduction and Targeted Therapy. 2022, 7(1): 181.
- Powell, C. E., et al. Chemically induced degradation of anaplastic lymphoma kinase (ALK). Journal of Medicinal Chemistry. 2018, 61(9): 4249-4255.
* PROTAC® is a registered trademark of Arvinas Operations, Inc., and is used under license.
