Source: PharmSnap
Written by: balabala Edited by: ohooIn July 2001, Professor Craig Crews from Yale University and Professor Raymond Deshaies from the California Institute of Technology published a paper in the journal *Proc Natl Acad Sci U S A*, in which they first introduced the concept of Proteolysis Targeting Chimera (PROTAC).
In the following two decades, PROTAC new drug research and development has made significant progress. PROTAC technology, with its innovative approach at the source of drug design, overcomes the challenge of developing traditionally "undruggable" targets, redefining small-molecule drugs and being considered a "revolutionary technology" in the biopharmaceutical field.
PROTAC is a heterobifunctional small molecule composed of three parts: a target protein (POI) ligand, a linker, and an E3 ligase ligand. After the PROTAC molecule enters the cell, its two ends bind to the target protein and the E3 ligase respectively, forming a POI-PROTAC-E3 Ligase ternary complex. This induces proximity between the E3 ligase and the POI, leading to POI ubiquitination. Eventually, the POI is recognized and degraded by the intracellular 26S proteasome. To date, more than 20 PROTACs have entered clinical trials worldwide.
In recent years, some pharmaceutical companies in China, such as BeOne Medicines, Haisco, Hinova pharma, and Kintor Pharmaceuticals, have already laid out plans in the PROTAC field. According to statistics from company announcements and press releases, as of now, there are already 16 domestically produced PROTACs in clinical stages, but no PROTAC has yet entered a pivotal or Phase 3 clinical trial.
In terms of clinical initiation timelines, in 2021, three companies—Hinova Pharma, BeOne Medicines, and Haisco—initiated clinical trials. In 2022, three more companies—Kintor Pharma, BeOne Medicines, and Accutar Biotechnology—began their clinical trials. By 2023, the pace of clinical initiations had accelerated significantly, with as many as 11 clinical trials launched. This indicates that as PROTAC technology gradually gains validation, pharmaceutical companies in China are progressively increasing their investments in the protein degradation field.
Figure 1. PROTAC Pipeline in Clinical Stage of Pharmaceutical Companies in China
BeOne Medicines Launches World-Leading BTK Degrader BGB-16673,
More effective than Nurix's competing products
BeOne Medicines was founded in 2010 as a global biotechnology company dedicated to discovering and developing innovative anti-cancer drugs for cancer patients worldwide. Its focus has gradually expanded from lymphoma to leukemia and multiple myeloma, forming a hematology oncology portfolio centered around its core product BRUKINSA® (zanubrutinib), along with promising pipeline drugs such as the BCL-2 inhibitor and BTK CDAC (BGB-16673).
Figure 2. BeOne Medicines R&D PipelineBGB-16673 is an orally available chimeric degrader compound targeting BTK, designed to degrade both wild-type BTK and multiple mutant forms of BTK. Preclinical study data show that BGB-16673 exhibits favorable pharmacological properties, high potency and selectivity, good oral bioavailability, and a long half-life. It was well-tolerated in animal studies. Additionally, BGB-16673 has the potential to overcome resistance mutations such as BTK C481S, T474, and L528W. Mouse models demonstrated that BGB-16673 exhibited stronger inhibition of C481S mutant tumors compared to Eli Lilly's non-covalent BTK inhibitor pirtobrutinib.Global Phase 1 clinical dose-escalation data for BGB-16673 indicate that the ORR of BGB-16673 in BTKi-resistant CLL/SLL patients is 70% (N=10), surpassing Nurix's similar products NX-2127 (ORR=41%, N=27) and NX-5948 (ORR=43%, N=7).In terms of safety, BGB-16673 demonstrated a favorable safety profile in patients who had received multiple prior lines of therapy. The MTD was not reached, and no cases of atrial fibrillation or hypertension were observed. Additionally, the incidence of Grade 3 neutropenia with BGB-16673 (15.4%) was lower than that reported for NX-2127/NX-5948 at 42.6%/19.2%. The company plans to initiate a Phase 2 dose expansion study in patients with CLL/SLL and MCL.Figure 3. Tolerability Data of BGB-16673
Figure 4. Efficacy and Safety Data of BGB-16673Hinova Pharma's HP518 Takes the Lead in China,
May Become China's First Oral AR Degrader?
Hinova Pharma focuses on the research and development of innovative drugs in major therapeutic areas such as cancer and metabolic diseases, with four core technology platforms: "PROTAC Targeted Protein Degradation Technology Platform, Deuterated Drug Research and Development Platform, Targeted Drug Discovery and Validation Platform, and Translational Medicine Technology Platform."In the fields of cancer and metabolic diseases, a product pipeline with 13 research products has been established. The core product, HC-1119 for the treatment of prostate cancer, has submitted a new drug application for market approval, and three products have entered different stages of clinical trials (HC-1119, HP518, HP501).
Figure 5. Hinova Pharma R&D PipelineHP518 is the first domestically produced oral AR PROTAC drug candidate in China to enter the clinical stage, with the potential to address AR mutation-induced drug resistance in prostate cancer. HP518 demonstrates favorable oral exposure and bioavailability in animal models. It exhibits high degradation activity against both wild-type AR and enzalutamide-resistant mutant AR, shows high selectivity for AR, and displays excellent anti-tumor activity in AR-dependent prostate cancer cell lines. Additionally, HP518 has shown superior efficacy in animal models of prostate cancer.Currently, the Phase I clinical trial of HP518 is being conducted in Australia. The first patient was enrolled in January 2022 for the Phase Ia dose-escalation study of HP518 in Australia. The Phase I clinical data from Australia was first presented at the 2024 American Society of Clinical Oncology Genitourinary Cancers Symposium (ASCO-GU). The Phase I clinical results showed positive signals, with overall good drug safety and no significant adverse events reported.Moreover, the clinical trial application for HP518 with the same indication has been approved by the U.S. FDA, and the clinical trial application in China was approved by the NMPA in November 2023, with the first patient dosed in China in December 2023. The Phase I clinical research results of HP518 in Australia being selected for the 2024 ASCO also signify that the relevant clinical research data has been recognized by a top international academic conference, and HP518 is expected to become a new-generation treatment for prostate cancer.Figure 6. Anti-tumor activity results of HP518 in mouse modelsHaisco's Self-Developed PROTAC Platform Yields Abundant Results,
Three Drugs Enter Clinical Stage
Haisco Takes the Lead in China to Layout the Cutting-edge PROTAC Technology Platform. Aiming to develop First-in-class, highly selective, and orally effective protein degradation drugs for tumors and autoimmune diseases, the company has so far deployed dozens of PROTAC projects. Currently, there are three PROTAC drugs in Phase 1 clinical trials under development: HSK29116 (BTK-PROTAC), HSK40118 (EGFR-PROTAC), and HSK38008 (AR-PROTAC).Figure 7. Haisco PROTAC R&D PipelineHSK29116 is the first oral BTK-PROTAC small molecule anti-tumor drug in China and the second in the world to enter clinical trials. Compared with ibrutinib, the world's first marketed BTK inhibitor, HSK29116 demonstrates stronger target selectivity and higher drug sensitivity. The first patient was enrolled in August 2021, and it is expected to become a first-in-class drug.Figure 8. Comparison of Target Selectivity between HSK29116 and IbrutinibHSK40118 is an orally administered EGFR-PROTAC small molecule anti-tumor drug independently developed by Haisco. It is the second small molecule anti-tumor drug selected from Haisco's leading PROTAC R&D platform and is intended for clinical use in treating advanced non-small cell lung cancer (NSCLC) with EGFR mutations. Currently, the NSCLC indication is in Phase 1 clinical trials. The first patient was enrolled in March 2023, with plans to enroll 220 EGFRi-resistant NSCLC patients.HSK38008 Oral Formulation is the world's first orally-administered AR-V7 degrader independently developed by Haisco, intended for the treatment of prostate cancer. Cell proliferation assay results demonstrate that HSK38008 significantly inhibits cell proliferation in AR-V7 positive cell lines (such as 22RV1) and exhibits a synergistic anti-proliferative effect on VCAP (human prostate cancer cells) when used in combination with enzalutamide.In terms of in vivo efficacy, in the 22RV1 castrated mouse xenograft model with AR-V7 mutation, HSK38008 dose-dependently inhibited tumor growth, with a TGI of 89.8% at 10 mpk and complete tumor regression observed at 30 mpk, showing significantly superior efficacy compared to ARV-110 and enzalutamide. The drug is currently in Phase 1 clinical trials, with the first patient enrolled in April 2023. A total of 99 mCRPC patients are planned for enrollment.Other pharmaceutical companies in China, such as Hengrui Pharma, Betta Pharmaceuticals, and Qilu Pharmaceutical, have also made arrangements in the field of protein degradation drugs. This indicates that PROTAC technology has strong development potential in clinical treatment and market space, and the future is promising.Looking ahead, the development potential of PROTAC technology is enormous. Many pharmaceutical companies in China are actively entering the field of protein degradation drugs, collectively promoting the clinical application and market expansion of this technology. We have good reason to believe that, in the near future, PROTAC drugs will play an increasingly important role in clinical treatment and market space, contributing more to the cause of human health.
References
1. BeOne Medicines, Hinova pharma, Haisco Pharmaceutical Group Official Websites, Announcements
2. Deutsche Bank Securities Research Report, Pacific Securities Research Report
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