Aug 2026· European Journal of Pharmaceutical Sciences· pp.
107633
· 0 citations· 31 references
Medicine
TL;DR
This work designed and synthesized 20 novel KRAS G12D PROTACs based on the MRTX1133 derivative and found that compound VI-1 exhibited significant KRAS G12D degradation activity in PANC-0203 cells, achieving 69% effective degradation at 10 μM.
Abstract
KRAS-G12D has long been regarded as an intractable therapeutic target due to the flat binding pocket and its strong affinity for GTP/GDP. Proteolysis-targeting chimera (PROTAC) is a revolutionary drug discovery strategy that, by virtue of its unique pharmacological mode of action, provides more options for targeting undruggable targets. In this study, we designed and synthesized 20 novel KRAS G12D PROTACs based on the MRTX1133 derivative. Through systematic exploration of linker structure-activity relationship and multi-cell line screening, compound VI-1 exhibited significant KRAS G12D degradation activity in PANC-0203 cells, achieving 69% effective degradation at 10 μM. Notably, the preferred compounds exhibited significant selectivity for other KRAS mutations and normal cells. This work provides an important lead compound for developing highly selective KRAS G12D PROTACs and warrants further exploration in the context of drug-likeness optimization.
Targeting diverse KRAS mutations with a single agent remains a significant challenge in oncology. Here, we report the discovery and characterization of RP04340, a potent and orally bioavailable pan-KRAS PROTAC degrader. Starting with a structure-based pan-KRAS inhibitor capable of forming a critical hydrogen bond with Tyr96, systematic optimization led to a PROTAC with broad-spectrum KRAS degradation, oral bioavailability, and drug safety profiles. RP04340 potently degrades multiple KRAS mutants, without affecting HRAS, NRAS, or known CRBN neosubstrates, and exhibits robust antiproliferative activity in various cancer cell lines. Orally administered in mice, RP04340 shows sustained exposure, leading to KRAS degradation and downstream signaling suppression. In mouse xenograft models (KRAS G12C, G12D, and G12V), once-daily oral administration of RP04340 resulted in tumor regression and longer-lasting tumor suppression compared to the clinical-stage pan-RAS inhibitor RMC-6236. With its promising efficacy and druglike properties, RP04340 represents a compelling candidate for KRAS-driven cancers.
Xiang Ji, Yue-Ning Du, Qi-Guo Zhang et al.· Journal of Medicinal Chemist...· 0 citations
KLHL12 is identified as a potentially tumor-selective E3 ligase and the development of the first-in-class KLHL12-recruiting PROTACs are reported, which established KLHL12 as a promising tumor‑selective E3 ligase and provided a KLHL12-recruiting PROTAC platform for cancer therapy.
Shicheng Xu, Xian Zhang, Shun-Bo Hu et al.· Angewandte Chemie· 0 citations
This work developed panKRAS degraders using a structure-guided strategy combining reversible KRAS binders with VHL-recruiting PROTACs and enables potent pan-allelic degradation, including ON-biased mutants, establishing KRAS degradation as a viable therapeutic modality and positioning ACBI4 as a pioneering panKRAS ON/OFF chemical probe.
A. Mantoulidis· Clinical Cancer Research· 0 citations
Aurora kinases, especially AURKA, are critical for mitotic regulation, and their dysregulation is linked to tumorigenesis, making AURKA a promising anticancer target. Conventional ATP-competitive AURKA inhibitors suffer from low subtype selectivity and failure to disrupt noncatalytic functions, resulting in limited therapeutic efficacy and substantial toxic side effects. Proteolysis-targeting chimera (PROTAC) technology presents a promising alternative by enabling degradation of the target protein, thereby blocking both catalytic and noncatalytic functions. Here, we developed AURKA degraders based on the allosteric inhibitor CAM2602 and CRBN-recruiting moieties. Compound CT3 was characterized as a potent and subtype-selective AURKA degrader. It displayed enhanced antiproliferative activity compared with the parental inhibitor in Jurkat cells, which have high CRBN and AURKA expression, and demonstrated effective in vivo antitumor effects in Jurkat xenograft models. Further structural optimization is expected to generate promising AURKA degrader candidates for drug development.
Yuanna Ye, Yalan Feng, Hao Wang et al.· Journal of Medicinal Chemist...· 0 citations
The prolyl isomerase Pin1 is a critical regulator of protein conformation and is frequently overexpressed across a spectrum of human malignancies. Its enzymatic activity is essential for stabilizing numerous oncogenic client proteins while promoting the turnover of key tumor suppressors, thereby driving neoplastic cell survival, proliferation, and therapeutic resistance. Targeting Pin1 offers a promising therapeutic strategy to address pancreatic ductal adenocarcinoma (PDAC).
We describe the discovery and characterization of a selective heterobifunctional degrader targeting Pin1. We hypothesized that complete protein elimination, rather than enzymatic inhibition alone, would deliver a more profound and durable anti-tumor response. We have developed an in vivo tool molecule, characterized by rapid in vitro degradation kinetics, single-digit nM DC50 activity in rodent cellular systems, and proteome-wide selectivity confirmed by whole-cell proteomics (WCP) across multiple cell lines. We report that this optimized tool has pharmacokinetic characteristics suitable for in vivo studies. In addition, treatment with Pin1 degraders induces deep and sustained degradation of Pin1 in vivo. Finally, we report single agent efficacy in in PDAC in vivo models.
We have developed a highly selective, first-in-class Pin1 degrader which demonstrated robust PKPD in vivo with sustained target engagement observed following a single dose. We also demonstrate that Pin1 degraders drive significant tumor growth inhibition (TGI) across multiple PDAC efficacy models.
Morgan B. O'Shea, Guosen B. Ye, Melvyn B. Chow, Lilly B. Ein, Julie B. Arnold, Jessica Freda, Erica Dube, Pradeep B. Kota, Swanny B. Lamboy-Rodriguez, Scott B. Eron, Catherine B. Sabatos-Peyton, Andrew Good, Eva B. d'Hennezel, Krista Goodman. A first-in-class Pin1 degrader provides robust PKPD response and efficacy in PDAC models [abstract]. In: Proceedings of AACR Drug Discovery and Development (AACR D3) Conference; 2026 Jul 21-24; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(14_Suppl):Abstract nr PR011.
Morgan B. O'Shea, Guosen B. Ye, Melvyn B. Chow et al.· Clinical Cancer Research· 0 citations
Targeted protein degradation (TPD) represents a promising approach for eliminating disease-causing proteins beyond traditional inhibition. However, the reliance on a limited number of E3 ligases remains a major bottleneck. FEM1B, an E3 ligase substrate receptor with multiple substrate-recognition modes, represents an attractive but underexplored TPD platform. In this study, through a structure-guided approach exploiting the spatial proximity between a druggable C-degron-binding pocket and a second binding site containing a reactive cysteine, we developed FL47, a dual-site ligand that combines extensive noncovalent interactions with targeted covalent engagement. FL47 exhibits submicromolar affinity, robust cellular target engagement, and markedly reduced cytotoxicity relative to previously reported covalent recruiters. We further applied FL47 in the development of FEM1B-based PROTACs and incorporated a chemical endocytic prodrug strategy that markedly enhanced degradation activity. This work introduces a novel dual-site binding strategy for E3 ligase ligand discovery and broadens the potential toolbox for TPD applications.
Ling-xiang Xu, Ruyi Huang, Yuying Ma et al.· Journal of Medicinal Chemist...· 0 citations
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