Cereblon (CRBN)-based molecular glue degraders (MGDs) have emerged as one of the most rapidly evolving therapeutic modalities in targeted protein degradation. Upon binding of MGDs such as immunomodulatory drugs, CRBN undergoes an allosteric transition into a degradation-competent closed conformation, enabling the recruitment of structurally compatible neosubstrates for subsequent ubiquitination and proteasomal degradation. Recently, the repertoire of CRBN neosubstrates has rapidly expanded beyond the classical IMiD neosubstrates such as IKZF1/3 and CK1α. In particular, many therapeutically relevant protein kinases have been identified as CRBN neosubstrates including WEE1, NEK7, CDK2, CDK4, mTOR, LCK, ALK, TBK1, and IRAK1. Moreover, structural analyses of recently developed, potent and selective kinase MGDs have demonstrated that kinase recruitment extends far beyond the canonical β-hairpin G-loop degron. It encompasses diverse structural elements including α-helical G-loop degrons, αC helix glutamate, α-helical degron surfaces, and protein complex composite surfaces. These unique, target-specific engagement modes underpin the exceptional selectivity of these novel kinase degraders. Furthermore, because CRBN-based kinase MGDs deplete both the enzymatic and non-catalytic functions of target kinases, kinase MGDs can overcome resistance associated with conventional ATP-competitive kinase inhibitors and enhance therapeutic efficacy, particularly in combination therapies. This review provides a comprehensive overview of recent advances in CRBN-based kinase MGDs, highlighting compound optimization, structural basis of kinase recognition, mechanisms of action, and therapeutic potential.
Chronic hepatitis B virus (HBV) infection is a serious public health burden, and current treatments fail to achieve satisfactory cure rates. RG7834 is a novel therapeutic agent with a differentiated mechanism of action (MOA) compared to current standard treatments. However, its Phase I clinical trial was terminated due to neurotoxicity issues. Furthermore, the pharmacokinetic performances of RG7834 are unsatisfactory, leaving significant room for improvement. This article reports some attempts and efforts based on the RG7834 molecule, including enhancing antiviral activity, improving pharmacokinetic performance in various genera. Ultimately, we obtained a preferred molecule 42 that, compared with RG7834, exhibited stronger in-vitro antiviral activity and significantly better pharmacokinetic performance in dogs, and cynomolgus monkeys. 42 demonstrated strong in vivo anti-HBV activity in an AAV/HBV mouse model, warranting further investigation.
Breast cancer is the most prevalent cancer globally, accounting for 18% of all cancers in women. Majority of breast cancers (75%) are associated with over-expression of estrogen receptors (ER). In this report, two ER-targeting peptides were synthesized manually on solid phase. The ER-affine pentapeptide motif LHRLL was conjugated with cell penetrating cationic amino acid sequence, RRRRK to obtain the peptide construct ERK (RRRRKILHRLLQDS-NH2) and a cyclic variant cERK (RRRRKCLHRCLQDS). The two peptides were conjugated with DOTA chelator and radiolabeled with Lu-177. [177Lu]Lu-DOTA-ERK and [177Lu]Lu-DOTA-cERK showed high binding affinity (~30 nM) towards human breast carcinoma MCF-7 cells. High cellular internalization was observed for the two radiopeptides. The cyclic variant, [177Lu]Lu-DOTA-cERK exhibited higher human serum stability and metabolic stability in mouse urine sample. Higher tumor uptake and tumor-to-organ ratios were presented by [177Lu]Lu-DOTA-cERK. This first attempt of evaluation of LXXLL motif radiopeptide will broaden the scope of synthesis of diverse ligands with improved biological profile.
The 5-lipoxygenase-activating protein (FLAP) is an essential regulator of leukotriene (LT) biosynthesis, a pathway implicated in both chronic inflammation and tumor progression. Building on our benzimidazole lead, whose FLAP potency was compromised by prior structural modifications, we systematically remodeled the scaffold at the C(5) and C(2) positions to define the precise steric, electronic and polarity requirements for cellular FLAP inhibition. A structurally diverse library of derivatives was synthesized and evaluated in intact human polymorphonuclear leukocytes. Structure-activity relationship analysis revealed that conventional aromatic motifs within the address region are fully replaceable by polar, sterically hindered aliphatic substituents, yielding highly potent FLAP inhibitors. Conversely, the core bioisostere region proved considerably more restrictive, strongly favoring the parent aliphatic motif and tolerating only neutral, non-basic replacements. Comprehensive lipid mediator profiling in primary human leukocytes and distinct macrophage phenotypes confirmed that the optimized analogues selectively suppress FLAP-dependent leukotrienes while leaving alternative arachidonic acid metabolic pathways largely unaffected. Parallel screening against glioblastoma, breast, and colon carcinoma lines uncovered an additional, independent antiproliferative activity intrinsic to the benzimidazole scaffold. Several analogues successfully combined robust cellular FLAP inhibition with significant growth inhibition, particularly against colon cancer cells. Because antiproliferative efficacy did not correlate with FLAP inhibition across the series, the data establish that these complementary pharmacological activities are mechanistically distinct and independently tunable. Ultimately, these dual-action agents offer a promising novel chemotype for modulating the pro-inflammatory tumor microenvironment, providing a clear foundation for future mechanistic investigations to identify their specific distinct anticancer targets.
