Aug 2026· Angewandte Chemie· pp.
e3312795
· 0 citations· 24 references
Medicine
TL;DR
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.
Abstract
Proteolysis-targeting chimeras (PROTACs) are currently constrained by a reliance on ubiquitously expressed E3 ligases, which compromises tumor selectivity and raises toxicity risks. Here, we identified KLHL12 as a potentially tumor-selective E3 ligase and reported the development of the first-in-class KLHL12-recruiting PROTACs. Guided by a structure-based macrocyclization strategy, we obtained a high‑affinity cyclic peptide, cp4, as a KLHL12‑binding ligand and constructed novel PROTACs against oncogenic BRD4 and EGFR. The optimal compound k12bp-1 achieved tumor-selective BRD4(L) degradation in A549 cells, significantly inhibiting cell proliferation and driving cell apoptosis while sparing normal cells. It demonstrated robust in vivo antitumor efficacy in A549 xenograft mouse models without observable systemic toxicity. Collectively, this work established KLHL12 as a promising tumor‑selective E3 ligase and provided a KLHL12-recruiting PROTAC platform for cancer therapy.
ABSTRACT Targeted protein degradation represents a promising therapeutic strategy, yet its broader application is often limited by the scarcity of usable E3 ligases. Glutathione peroxidase 4 (GPX4) is a key target for inducing ferroptosis, but achieving sustained and potent inhibition remains challenging with conventional enzymatic inhibitors. Herein, we report the first small‐molecule GPX4 degraders that incorporate either electrophilic warheads or a minimal azide group as an E3 recruitment ligand. The azide‐based degrader DK‐5070 effectively drives potent GPX4 degradation, achieving a DC50 of 17.4 nM and a Dmax of 84%, thereby outperforming larger PROTAC‐based degraders. Notably, DK‑5070 exhibits potent antitumor activity both in vitro (IC50 = 47.21 nM) and in vivo (TGI = 41.8%), demonstrating significant efficacy as a GPX4 degrader. Mechanistic studies reveal that degradation is mediated through recruitment of the oncogenic E3 ligase UHRF1, which is frequently overexpressed in tumors, underscoring the potential for tumor‐specific protein degradation. This demonstrated small‐molecule degraders that recruit UHRF1 to facilitate targeted degradation of GPX4. In this system, the azide group functions as a minimal recruitment ligand, thereby expanding the E3 ligase toolbox and offering a promising strategy for targeted cancer therapy.
Zehong Lin, Kang Duan, Rui Wan et al.· Advancement of science· 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
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 B046.
Morgan B. O'Shea, Guosen B. Ye, Melvyn B. Chow et al.· Clinical Cancer Research· 0 citations
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.
Lili Jiang, Wenyan Yang, Yanqing Liu et al.· European Journal of Pharmace...· 0 citations
This work reports the first ligand-directed chemical strategy that converts transient PROTAC-mediated ternary complex formation into binary target recognition via post-translational chemical modification of an E3 ligase, and believes it could provide a platform for next-generation targeted protein degraders to overcome the current limitation of PROTAC approach.
Eunbin Park, Jinjoo Jung, Gangasani Jagadeesh Kumar et al.· Bioorganic chemistry (Print)· 0 citations
This review summarizes recent advances in chemical protein degradation strategies for neurodegenerative disorders and highlights potential future perspectives of multifunctional PROTACs for therapeutic development.
Pasquale Degennaro, Imane Ghafir El Idrissi, Rosa Purgatorio et al.· Pharmaceuticals· 0 citations
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