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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 I

1. Arvinas

Founded in 2013 by Craig Crews, a pioneer in the field of targeted protein degradation, Arvinas focuses on oncology and central nervous system diseases, making it one of the most prominent companies in the PROTAC space. Currently, Arvinas has multiple candidates in development, including ARV-471 (vepdegestrant) in Phase 3 clinical trials, as well as ARV-110 and ARV-766 in Phase 2.

1.1) ARV-471 – The First PROTAC Star Molecule to Enter Phase III Clinical Trials

The primary application involves MCF7 cells, with an ER DC50 reference value of 1.8 nM. Other potentially applicable cell lines include: MB-134-VI, T47D, D538G, Y537S, ZR-75-1, BT474, and CAMA-1 [1].

ARV-471 (Vepdegestrant) is a PROTAC product co-developed and commercialized with Pfizer. It is a CRBN-based estrogen receptor PROTAC degrader for the oral treatment of patients with estrogen receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative (ER+/HER2-) locally advanced or metastatic breast cancer. The product is currently in Phase III clinical studies, with recent updates on its Phase III clinical progress.

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1.2) ARV-766 – A PROTAC Degrader Targeting AR Protein Including the L702H Mutation

The degradation effect of ARV-766 on AR in WT LNCaP and VCaP cells is as follows: LNCap DC50 = <1.3 nM; Dmax >91%; VCaP DC50 = <1 nM; Dmax >94% [4].

ARV-766 is Arvinas' second-generation orally bioavailable PROTAC androgen receptor (AR) degrader for prostate cancer patients, currently in Phase II clinical trials. Compared to the first-generation ARV-110, ARV-766 demonstrates degradation capability against multiple mutant subtypes, including H875Y and T878A, while effectively degrading the AR L702H mutation [2]. The AR L702H mutation represents a common resistance mechanism in CRPC patients [3]. This product is co-developed and commercialized in collaboration with Novartis.

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2. Kymera

Kymera Therapeutics was established in May 2017 and went public on the NASDAQ in August 2020. The company focuses on the fields of autoimmunity and oncology, targeting inflammation-related proteins such as IRAK4, STAT6, TYK2, and MDM2. Its target selection is strategic—for example, KT-474's target IRAK4 possesses both kinase and scaffolding functions, while KT-333's target STAT3 currently has no approved drugs. Additionally, the company has developed an integrated TPD drug discovery platform called Pegasus™, which has extensively studied the expression profiles of over 600 E3 ligases across various cells and tissues, identifying multiple specifically expressed E3 ligases.

2.1) KT-474 – The First PROTAC in Autoimmune Disease Research to Trigger Sanofi's Milestone Payment

Mainly used in immune cells, Lymphocytes - IRAK4 DC50=1.8 nM; Monocytes - IRAK4 DC50=2.6 nM [5]

KT-474 is a first-in-class IRAK4 degrader for the treatment of hidradenitis suppurativa (HS), atopic dermatitis (AD), and other potential diseases. IRAK4 is a scaffolding kinase that operates at the interface of innate and adaptive immune responses, performing multiple functions through both its kinase activity and scaffolding role. By completely eliminating IRAK4 through degradation, both kinase and scaffolding functions are affected, potentially enabling broad and well-tolerated anti-inflammatory effects. KT-474 is being co-developed with Sanofi and is currently in Phase II clinical trials.

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2.2) KT-333 – Targeting the Undruggable STAT3 with Orphan Drug and Fast Track Designations

Applicable cell lines: DC50=2.5-11.8 nM in ALCL lines; other applicable cells include SU-DHL-1 cells and human PBMCs [6].

KT-333 is a potent, highly selective STAT3 degrader being developed for various STAT3-dependent conditions, including hematologic malignancies and solid tumors. In the anaplastic large cell lymphoma (ALCL) cell line SU-DHL-1, KT-333 selectively degraded STAT3 among over 8,000 rigorously quantified proteins (including all other six STAT family proteins). The drug is currently in Phase I clinical trials.

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2.3) KT-253 – Overcoming the p53-MDM2 Negative Feedback Loop and Securing Orphan Drug Designation

RS4-11, IC50=0.3 nM; MDM2-HiBiT, DC50=0.4 nM [7].

p53 is the most significant tumor suppressor. In cancers with wild-type p53, p53 activity is regulated by MDM2. MDM2 can ubiquitinate p53, leading to its degradation, and overexpression or amplification of MDM2 can inactivate p53. Current investigational small-molecule MDM2 inhibitors have shown limited clinical benefits, likely due to the negative feedback loop in which MDM2 is both induced by p53 and subsequently suppresses p53 activity—when p53 is upregulated, MDM2 protein levels also increase. In preclinical studies, KT-253 has demonstrated the ability to overcome this negative feedback loop, rapidly inducing cancer cell death after brief exposure. This suggests potential advantages in efficacy and safety over small-molecule inhibitors. The drug is currently in Phase I clinical trials.

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