Multiple studies have demonstrated that cancer cells with microsatellite instability (MSI) are intolerant to loss of the Werner syndrome helicase (WRN), whereas microsatellite-stable (MSS) cancer cells are not. Therefore, WRN represents a promising new synthetic lethal target for developing drugs to treat cancers with MSI. Given the uncertainty of how effective inhibitors of WRN activity will prove in clinical trials, and the likelihood of tumours developing resistance to WRN inhibitors, alternative strategies for impeding WRN function are needed. Proteolysis-targeting chimeras (PROTACs) are heterobifunctional small molecules that target specific proteins for degradation. Here, we engineered the WRN locus so that the gene product is fused to a bromodomain (Bd)-tag, enabling conditional WRN degradation with the AGB-1 PROTAC specific for the Bd-tag. Our data revealed that WRN degradation is highly toxic in MSI but not MSS cell lines. In MSI cells, WRN degradation caused G2/M arrest, chromosome breakage and ATM kinase activation. We also describe a multi-colour cell-based platform for facile testing of selective toxicity in MSI versus MSS cell lines. Together, our data show that a degrader approach is a potentially powerful way of targeting WRN in MSI cancers and paves the way for the development of WRN-specific PROTAC compounds.

Triple-negative breast cancer is one of the most malignant subtypes in clinical practice, and it is urgent to find new therapies. The p21-activated kinase I (PAK1) has been considered to be an attractive therapeutic target for TNBC. In this study, we designed and synthesized a series of novel PROTAC PAK1 degraders by conjugating VHL or CRBN ligase ligands to PAK1 inhibitors which are connected by alkyl chains or PEG chains. The most promising compound, 19s, can significantly degrade PAK1 protein at concentrations as low as 0.1 μM, and achieves potent anti-proliferative activity with an IC50 value of 1.27 μM in MDA-MB-231 cells. Additionally, 19s exhibits potent anti-migration activity in vitro and induces rapid tumor regression in vivo. Collectively, these findings document that 19s is a potent and novel PAK1 degrader with promising potential for TNBC treatment.

Abnormal activation of EGFR is often associated with various malignant tumors, making it an important target for antitumor therapy. However, traditional targeted inhibitors have several limitations, such as drug resistance and side effects. Many studies have focused on the development of EGFR degraders to overcome this resistance and enhance the therapeutic effect on tumors. Proteolysis targeting chimeras (PROTAC) and Lysosome-based degradation techniques have made significant progress in degrading EGFR. This review provides a summary of the structural and function of EGFR, the resistance, particularly the research progress and activity of EGFR degraders via the proteasome and lysosome. Furthermore, this review aims to provide insights for the development of the novel EGFR degraders.
[Box: see text].

Over the past two decades, molecular glues (MGs) have gradually attracted the attention of the pharmaceutical community with the advent of MG degraders such as IMiDs and indisulam. Such molecules degrade the target protein by promoting the interaction between the target protein and E3 ligase. In addition, as a chemical inducer, MGs promote the dimerization of homologous proteins and heterologous proteins to form ternary complexes, which have great prospects in regulating biological activities. This review focuses on the application of MGs in the field of drug development including protein-protein interaction (PPI) stability and protein degradation. We thoroughly analyze the structure of various MGs and the interactions between MGs and various biologically active molecules, thus providing new perspectives for the development of PPI stabilizers and new degraders.

Currently, antibody drugs targeting programmed cell death ligand 1 (PD-L1) have achieved promising results in cancer treatment, while the development of small-molecule drugs lags behind. In this study, we designed and synthesized a series of PD-L1-degrading agents based on the PROTAC design principle, utilizing the PD-L1 inhibitor A56. Through systematic screening of ligands and linkers and investigating the structure-activity relationship of the degraders, we identified two highly active compounds, 9i and 9j. These compounds enhance levels of CD4+, CD8+, granzyme B, and perforin, demonstrating significant in vivo antitumor effects with a tumor growth inhibition (TGI) of up to 57.35 %. Both compounds facilitate the internalization of PD-L1 from the cell surface and promote its degradation through proteasomal and lysosomal pathways, while also maintaining inhibition of the PD-1/PD-L1 interaction. In summary, our findings provide a novel strategy and mechanism for developing biphenyl-based PROTAC antitumor drugs targeting and degrading PD-L1.

Bruton\'s tyrosine kinase (BTK) inhibitors have revolutionized the treatment landscape for B cell lymphomas such as chronic lymphocytic leukemia (CLL). The first-in-class BTK inhibitor ibrutinib has recently been succeeded by covalent BTK inhibitors that are safer but still face challenges of resistance mutations. The noncovalent BTK inhibitor pirtobrutinib was recently approved for relapsed and refractory CLL, and whether noncovalent BTK inhibitors will supplant covalent BTK inhibitors as upfront treatment options either alone or in combination will be determined. Meanwhile, newer BTK inhibitors and BTK degraders are vying for their place in the potential future landscape of B cell cancers as well as autoimmune diseases. This review will cover the latest progress in BTK inhibitor development and where the field is moving in light of these recent discoveries.

The androgen receptor (AR) is an attractive target for treating prostate cancer, considering its role in the development and progression of localized and metastatic prostate cancer. The high global mortality burden of prostate cancer, despite medical treatments such as androgen deprivation or AR antagonist therapy, highlights the need to explore alternative strategies. One strategy involves the use of heterobifunctional degraders, also known as proteolysis-targeting chimeras, which are novel small-molecule therapeutics that inhibit amplified or mutated targets. Here, the study reports a novel cereblon-based AR degrader, UBX-390, and demonstrates its superior activity over established AR degraders, such as ARV-110 or ARCC-4, in prostate cancer cells under short- and long-term treatment conditions. UBX-390 suppresses chromatin binding and gene expression of AR and demonstrates substantial efficacy in the degradation of AR mutants in patients with treatment-resistant prostate cancer. UBX-390 is presented as an optimized AR degrader with remarkable potential for treating castration-resistant prostate cancer.

About one-third of all human cancers encode abnormal RAS proteins locked in a constitutively activated state to drive malignant transformation and uncontrolled tumor growth. Despite progress in development of small molecules for treatment of mutant KRAS cancers, there is a need for a pan-RAS inhibitor that is effective against all RAS isoforms and variants and that avoids drug resistance. We have previously shown that the naturally occurring bacterial enzyme RAS/RAP1-specific endopeptidase (RRSP) is a potent RAS degrader that can be re-engineered as a biologic therapy to induce regression of colorectal, breast, and pancreatic tumors. Here, we have developed a strategy for in vivo expression of this RAS degrader via mRNA delivery using a synthetic nonviral gene delivery platform composed of the poly(ethylene glycol)-b-poly(propylene sulfide) (PEG-b-PPS) block copolymer conjugated to a dendritic cationic peptide (PPDP2). Using this strategy, PPDP2 is shown to deliver mRNA to both human and mouse pancreatic cells resulting in RRSP gene expression, activity, and loss of cell proliferation. Further, pancreatic tumors are reduced with residual tumors lacking detectable RAS and phosphorylated ERK. These data support that mRNA-loaded synthetic nanocarrier delivery of a RAS degrader can interrupt the RAS signaling system within pancreatic cancer cells while avoiding side effects during therapy.

UNASSIGNED: KRAS is a critical oncogenic protein intricately involved in tumor progression, and the difficulty in targeting KRAS has led it to be classified as an \'undruggable target.\' Among the various KRAS mutations, KRASG12D is highly prevalent and represents a promising therapeutic target, yet there are currently no approved inhibitors for it.
UNASSIGNED: This review summarizes numerous patents and literature featuring inhibitors or degraders of KRASG12D through searching relevant information in PubMed, SciFinder and Web of Science databases from 2021 to February 2024, providing an overview of the research progress on inhibiting KRASG12D in terms of design strategies, chemical structures, biological activities, and clinical advancements.
UNASSIGNED: Since the approval of AMG510 (Sotorasib), there has been an increasing focus on the inhibition of KRASG12D, leading to numerous reports of related inhibitors and degraders. Among them, MRTX1133, as the first KRASG12D inhibitor to enter clinical trials, has demonstrated excellent tumor suppression in various KRASG12D-bearing human tumor xenograft models. It is important to note, however, that understanding the mechanisms of acquired resistance caused by KRAS inhibition and developing additional combination therapies is crucial. Moreover, seeking covalent inhibition of KRASG12D also holds significant potential.

Molecular glue (MG) degraders include plant hormones and therapeutic drugs and have become a hot topic in drug discovery. Unlike bivalent proteolysis targeting chimeras (PROTACs), monovalent MGs can trigger the degradation of non-ligandable proteins by enhancing their interaction with E3 ubiquitin ligases. Here, I analyze the characteristics of natural MG degraders, contrast them with synthetic ones, and provide a rationale for optimizing MGs. In natural MG-based degradation systems, a stable complex is only formed when all three partners (MG, E3 ligase, and substrate) are present, while the affinities between any two components are either weak or undetectable. After the substrate is degraded, the MG will dissociate from its receptor (E3 ligase) due to their low micromolar affinity. In contrast, synthetic MGs, such as immunomodulatory drugs (IMiDs) and CR8, are potent inhibitors of their receptors by blocking the CRBN-native substrate interaction or by occupying the active site of CDK12. Inspired by nature, the affinities of IMiDs to CRBN can be reduced to make those compounds degraders without the E3-inhibitory activity, therefore, minimizing the interference with the physiological substrates of CRBN. Similarly, the CR8-CDK interaction can be weakened to uncouple the degrader function from the kinase inhibition. To mimic natural examples and reduce side effects, future development of MG degraders that lack the inhibitory activity should be considered.