Illustration of PROTAC mechanism for protein degradationIntroduction

PROTAC (PROteolysis TArgeting Chimera) is a novel therapeutic approach that leverages the cell’s natural protein degradation machinery to selectively target and degrade disease-causing proteins. Unlike traditional inhibitors that merely block the activity of a protein, PROTACs facilitate the complete removal of the target protein from the cell. This is achieved by a bifunctional molecule that binds to the target protein on one end and an E3 ubiquitin ligase on the other, bringing them into proximity and tagging the target protein for degradation by the proteasome. This method has shown promise in treating various cancers and other diseases by overcoming resistance mechanisms associated with traditional therapies. This news article highlights some of the innovative PROTAC drugs that were recently showcased at the 2024 meeting of the American Society of Gene & Cell Therapy (ASGCT).

Promising PROTAC Cancer Drugs on the Verge of Clinical Use

The table below provides an overview of several innovative PROTAC drug targets that are advancing towards clinical application.

PROTAC Target Company/Institution
Sterol Regulatory Element-binding Protein-1 (SREBP-1) MEDIFIC Inc.
Methyltransferase 3 (METTL3) Xijing Hospital Hunan University
Cyclin Dependent Kinase 4/6 (CDK4/6) Biotheryx Inc
SOS Ras/Rac Guanine Nucleotide Exchange Factor 1 (SOS1) Biotheryx Inc
Bruton Tyrosine Kinase (BTK) AbbVie Inc.
Androgen Receptor (AR) Hinova Pharma
Estrogen Receptor (ER) Eli Lilly and Company
MDM2 Kymera Therapeutics
Estrogen Receptor (ER) Eli Lilly and Company
Estrogen Receptor (ER) Accutar Biotechnology Inc.
Androgen Receptor (AR) Arvinas Androgen Receptor Inc.
Estrogen Receptor (ER) Pfizer Inc. Arvinas Estrogen Receptor Inc.

MFC0101 – SREBP1 Degrader for Glioblastoma

MFC0101 is a first-in-class SREBP1-targeted degrader developed by MEDIFIC Inc. It shows outstanding preclinical efficacy in synergy with temozolomide (TMZ) for treating glioblastoma multiforme (GBM). The degrader targets lipid metabolism pathways specific to glioblastoma stem cells, reducing the tumor-initiating capacity and showing complete tumor remission in preclinical models. Read more

RKL – METTL3 Degrader for Urothelial Carcinoma

RKL is a novel METTL3 peptide degrader that demonstrates synergistic effects with immune checkpoint inhibitors (ICI) in advanced urothelial carcinoma (aUC). Developed by researchers from Xijing Hospital and Hunan University, RKL targets the m6A methyltransferase METTL3, reducing tumor volume significantly and achieving high response rates in combination with ICI therapy. Read more

BTX-9341 – CDK4/6 Degrader for Breast Cancer and GBM

BTX-9341, developed by Biotheryx Inc., is a bifunctional degrader targeting CDK4 and CDK6 while inhibiting CDK2 and Cyclin E transcription. It shows enhanced activity compared to traditional CDK4/6 inhibitors in breast cancer and glioblastoma multiforme (GBM), suggesting a promising new therapeutic approach for these cancers. Read more

BTX-10908 – SOS1 Degrader for KRAS- and RTK-driven Cancers

BTX-10908 is an orally bioavailable SOS1 bifunctional degrader for KRAS- and RTK-driven cancers. Developed by Biotheryx Inc., it demonstrates robust activity in preclinical models, reducing tumor growth and enhancing the efficacy of existing therapies targeting the RTK-RAS-MAPK pathway. Read more

ABBV-101 – BTK Degrader for B-cell Malignancies

ABBV-101 is a potent, highly selective BTK degrader developed by AbbVie Inc. for treating relapsed/refractory B-cell malignancies. In preclinical and early clinical studies, ABBV-101 shows promise in overcoming resistance mechanisms associated with traditional BTK inhibitors, offering a new therapeutic option for B-cell cancers. Read more

HP518 – AR Degrader for Prostate Cancer

HP518, an androgen receptor (AR) PROTAC degrader developed by Hinova Pharma, shows encouraging results in a phase 1 study for metastatic castration-resistant prostate cancer (mCRPC). It degrades both wild-type and mutant AR, demonstrating promising safety and anti-tumor activity. Read more

Imlunestrant – SERD for Endometrial Cancer

Imlunestrant, developed by Eli Lilly and Company, is an oral selective estrogen receptor degrader (SERD) showing efficacy in endometrioid endometrial cancer (EEC). In combination with abemaciclib, it appears safe and tolerable with preliminary evidence of efficacy in metastatic ER+ EEC. Read more

KT-253 – MDM2 Degrader

KT-253, a novel MDM2 degrader developed by Kymera Therapeutics, shows potent upregulation of p53-dependent biomarkers and early anti-tumor activity in relapsed/refractory solid tumors and high-grade myeloid malignancies. It offers a new approach to targeting the p53-MDM2 feedback loop in cancer therapy. Read more

Imlunestrant – SERD Degrader

Imlunestrant in combination with HER2-directed therapies, developed by Eli Lilly and Company, demonstrates preliminary antitumor activity in ER+/HER2+ advanced breast cancer. This combination therapy is well-tolerated and shows no significant drug-drug interactions. Read more

AC699 – Chimeric ER Degrader

AC699, developed by Accutar Biotechnology Inc., is an orally bioavailable chimeric estrogen receptor degrader showing promising safety, tolerability, and anti-tumor activity in advanced breast cancer. Early results indicate potential for further clinical development. Read more

ARV-766 – AR Degrader

ARV-766, a PROTAC androgen receptor degrader developed by Arvinas Androgen Receptor Inc., shows promising clinical activity in metastatic castration-resistant prostate cancer (mCRPC). It targets both wild-type AR and clinically relevant AR mutations, suggesting further development in advanced prostate cancer. Read more

Vepdegestrant – ER Degrader for Breast Cancer

Vepdegestrant, a PROTAC estrogen receptor degrader in combination with the CDK4 inhibitor PF-07220060, shows promising early results in ER+/HER2- advanced breast cancer. This study, conducted by Pfizer Inc. and Arvinas Estrogen Receptor Inc., aims to evaluate the combination’s efficacy and safety. Read more

Conclusion

The development of PROTAC technology represents a major advancement in targeted cancer treatment. PROTACs use the body’s natural process to break down proteins, offering a new way to completely remove disease-causing proteins rather than just inhibiting them. This new type of drug is close to being used in clinical settings and holds promise for treating various cancers, including those that were previously difficult to target. The progress and expected success of PROTACs highlight a significant change in cancer treatment, pointing to a future where precision medicine can more effectively target and eliminate cancer.

Read our blog: Advancing PROTAC Therapeutics: Potency Assays for FDA Compliance