^®

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 II

3. Nurix Therapeutics

Nurix Therapeutics was established in 2009 and went public on NASDAQ on July 25, 2020. Founded by an internationally renowned team of experts in E3 ubiquitin ligase regulation and structure, Nurix possesses a unique DELigase targeted protein modulation platform combining E3 ligases with DNA-encoded small molecule libraries. The company focuses on developing drugs for oncology, immuno-oncology, adoptive cell therapy and immune disorders, with representative products including NX-2127, NX-5948 and NX-1607.

3.1) NX-2127 - A BTK + IKZF degrader for treating B-cell malignancies

In multiple cancer cell lines and human PBMCs, NX-2127 achieves BTK DC50 < 5 nM. In primary human T cells, NX-2127 mediates degradation of Aiolos and Ikaros with potencies of 25 nM and 54 nM respectively [1].

NX-2127 is an oral small molecule dual degrader targeting BTK and IKZF1 (Ikaros) and IKZF3 (Aiolos), which are associated with B-cell and T-cell activity. NX-2127 is used to treat patients with relapsed or refractory B-cell malignancies. The compound is currently in Phase I clinical trials.

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3.2) NX-5948 - A BTK Degrader for Treating B-Cell Malignancies

WT BTK at 4 hours (DC50=0.16 nM) and 24 hours (DC50=0.03 nM)[2]

Through further optimization and modification of NX-2127, the compound NX-5948 was developed. NX-5948 is an oral, CNS-penetrant, small-molecule BTK degrader currently being evaluated for chronic lymphocytic leukemia (CLL), non-Hodgkin lymphoma (NHL), and Waldenström's macroglobulinemia (WM). The product is now in Phase I clinical trials.

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4. C4 Therapeutics

C4 Therapeutics was founded in 2015 and became the fourth biotechnology company focused on targeted protein degraders to go public, following Arvinas, Kymera, and Nurix. The company's proprietary TORPEDO® platform originated from Dana-Farber Cancer Institute. Using this platform, C4T discovers and develops MonoDACTM and BiDACTM degraders, with BiDACTM being bifunctional degradation-activating complexes (i.e., PROTACs). The company secured 73 million in Series A financing in 2016 and 170 million in Series B financing in 2020, before going public on NASDAQ on October 1, 2020.

4.1) CFT1946 - A BRAF Degrader for Treating BRAF V600-Mutant Solid Tumors

BRAF-V600E ：DC50 = 14 nM[3]

CFT1946 is an orally bioavailable small-molecule degrader targeting BRAF V600 mutations. It is currently being evaluated in a global Phase I/II clinical trial for patients refractory to BRAF inhibitors. CFT1946 demonstrates efficacy and selectivity against BRAF V600 mutant forms. Preliminary clinical data from the Phase I trial indicate that CFT1946 has a favorable safety and tolerability profile, shows dose-dependent bioavailability and degradation of BRAF V600E protein, and provides evidence of antitumor activity as monotherapy.

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4.2) CFT8634 - A BRD9 degrader for treating synovial sarcoma and SMARCB1-deficient cancers

BRD9 DC50(2h)=3nM[4]

CFT8634 is a CRBN-based bifunctional molecule that selectively degrades BRD9, a protein essential for the proliferation of SMARCB1-mutant cancer cells. SMARCB1-mutant cancers include synovial sarcoma (carrying the SS18-SSX fusion gene) and SMARCB1-deficient cancers such as epithelioid sarcoma. After unsatisfactory data from a Phase I/II trial, C4 Therapeutics discontinued the development of this anticancer drug.

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