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In 2001, Craig M. Crews' team proposed PROTAC (Proteolysis Targeting Chimera), leveraging the cell's ubiquitin-proteasome system (UPS) for targeted protein degradation—a novel alternative to traditional inhibitors.

A major breakthrough came in 2015 with the first small-molecule PROTACs, proven effective in animal models. By 2019, Arvinas' ARV-110 and ARV-471 entered clinical trials, accelerating global PROTAC research and expanding preclinical pipelines.

The number of PROTACs in various stages of clinical trials over the past decade. (Source: Pharmaprojects Citeline Intelligence)

Technology and Strategic Positioning from Global PROTAC Leaders-Part III

5. Bristol Myers Squibb

In the field of protein degradation, Bristol Myers Squibb (BMS) rapidly became one of the leaders through its strategic acquisition of Celgene. The integration of Celgene brought BMS a rich R&D pipeline, particularly introducing the E3 ligase CRBN associated with protein degradation through products like lenalidomide. This enabled the development of numerous protein degraders, including star molecules such as Iberdomide (CC-220), Avadomide (CC-122), Mezigdomide (CC-885), and BMS-986365. Currently, BMS has built a pipeline covering oncology, immune diseases, neurodegenerative disorders, and other areas, with multiple products entering clinical stages.

5.1) BMS-986365 – The First PROTAC Drug Targeting AR to Enter Phase III Clinical Trials

It induces CRL4CRBN E3 ubiquitin ligase-dependent ubiquitination and degradation of AR (DC50: 10-40 nM), and can rapidly and profoundly degrade both wild-type and mutant AR in the cytoplasm or nucleus [1].

Originally developed by Celgene, BMS-986365 is an oral heterobifunctional degrader designed to inhibit AR activity through a first-in-class dual mechanism combining AR degradation and antagonism. It is the second protein-targeting chimera (PROTAC) drug globally to enter Phase III trials and the first PROTAC targeting the androgen receptor (AR) to reach this stage. Compared to existing AR antagonists like enzalutamide (ENZ), BMS-986365 demonstrates approximately 100-fold greater potency in suppressing androgen-stimulated AR target gene transcription and shows 10- to 120-fold enhanced efficacy in inhibiting AR-dependent proliferation across multiple prostate cancer cell lines.

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5.2) CC-220 – An Immunomodulatory CRBN Molecular Glue

The IC50 for cereblon binding affinity is approximately 150 nM [2].

CC-220 (Iberdomide), originally developed by Celgene, is an orally available cereblon (CRBN) E3 ubiquitin ligase immunomodulatory agent (CELMoD). It induces degradation of transcription factors IKZF1 (Ikaros) and IKZF3 (Aiolos) while suppressing tumor necrosis factor α (TNF-α) production. Currently, this compound has advanced to Phase III clinical trials for two indications.

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6. Other Companies' Star Products

6.1) DT2216 – A BCL-XL Degrader for Hematologic Malignancies and Solid Tumors

MOLT-4 T-cell DC50=63nM，Dmax=90.8%[3]

Developed by Dialectic Therapeutics, DT2216 is a novel anti-apoptotic protein-targeting degrader designed for hematologic malignancies and various solid tumors. It selectively induces degradation of the BCL-XL protein and represents a first-generation anti-apoptotic protein degrader for treating relapsed or refractory malignancies. The compound entered Phase I clinical trials in 2021.

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6.2) FHD-609 – A Potent BRD9 Degrader

BRD7 DC50=1.5 nM，BRD9 DC50=300 pM[4]

Developed by Foghorn Therapeutics, FHD-609 is a highly effective and selective BRD9 degrader that entered clinical trials for synovial sarcoma and SMARCB1-deficient cancers. Phase I trial data demonstrated FHD-609's ability to effectively degrade BRD9, but the trial was paused due to QTc interval prolongation observed at higher doses.

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6.3) ACBI3 – A KRAS Degrader Targeting "Undruggable" Targets

Antiproliferative activity in KRAS mutant vs. KRASWT cell lines (geometric mean IC50 = 478 nM and 8.3 μM respectively) [5]

KRAS is widely implicated in cancers and represents an important therapeutic target. However, due to its small protein size, high affinity for GTP, and lack of ideal binding pockets, KRAS has long been considered an "undruggable" target. In 2024, a collaborative study published in Science by Alessio Ciulli's team and Boehringer Ingelheim introduced ACBI3, a pan-KRAS degrader capable of selectively degrading 13 out of 17 common KRAS mutants.

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