Bioorganic & Medicinal Chemistry Letters最新文献

We discovered novel neuroprotective compounds by phenotypic screening using SOD1-mutant amyotrophic lateral sclerosis (ALS) patient induced pluripotent stem cell (iPSC)-derived motor neurons. Mechanistic analysis showed that the protective effect of initial hit compound 1 was likely due to the inhibition of MAP4Ks, including MAP4K4, a member of the MAP4K kinase family. Structural transformation led to compound 15f, which showed improved MAP4K4 inhibitory activity and superior neuroprotective effects compared to 1 in motor neurons. The results suggest that structural optimization based on MAP4K4 inhibitory activity might improve the neuroprotective effect of this series of compounds.

KAT6, a histone acetyltransferase from the MYST family, has emerged as an attractive oncology target due to its role in regulating genes that control cell cycle progression and cellular senescence. Amplification of the KAT6A gene has been seen among patients with worse clinical outcome in ER⁺ breast cancers. Although multiple inhibitors have been reported, no KAT6 inhibitors have been approved to date. Here, we report the fragment-based discovery of a series of N-(1-phenyl-1H-1,2,3-triazol-4-yl)benzenesulfonamide KAT6 inhibitors and early hit-to-lead efforts to improve the KAT6 potency.

Aminopeptidase A (APA) is a membrane-bound zinc metallopeptidase involved in the production of angiotensin III, one effector peptide of the brain renin-angiotensin system, making brain APA a relevant pharmacological target for the development of novel therapeutic treatments against hypertension and heart failure. The structure-based design of new APA inhibitors is described, based on previously developed thiol-containing inhibitors and APA crystal structure. Chemical synthesis, in vitro assessment against APA activity, pharmacological and pharmacokinetic profiling were performed, ultimately leading to a potent and selective APA inhibitor.

A novel series of 3-amino-piperidin-2-one-based calcitonin gene-related peptide (CGRP) receptor antagonists was invented based upon the discovery of unexpected structure–activity observations. Initial exploration of the structure–activity relationships enabled the generation of a moderately potent lead structure (4). A series of modifications, including ring contraction and inversion of stereocenters, led to surprising improvements in CGRP receptor affinity. These studies identified compound 23, a structurally novel potent, orally bioavailable CGRP receptor antagonist.

Emerging clinical evidence indicates that selective CDK9 inhibition may provide clinical benefits in the management of certain cancers. Many CDK9 selective inhibitors have entered clinical developments, and are being investigated. No clear winner has emerged because of unforeseen toxicity often observed in clinic with these agents. Therefore, a novel agent with differentiated profiles is still desirable. Herein, we report our design, syntheses of a novel azaindole series of selective CDK9 inhibitors. SAR studies led to a preclinical candidate YK-2168. YK2168 exhibited improved CDK9 selectivity over AZD4573 and BAY1251152; also showed differentiated intravenous PK profile and remarkable solid tumor efficacy in a mouse gastric cancer SNU16 CDX model in preclinical studies. YK-2168 is currently in clinical development in China (CTR20212900).

High levels of extracellular adenosine in tumor microenvironment (TME) has extensive immunosuppressive effect. CD73 catalyzes the conversion of AMP into adenosine and regulates its production. Inhibiting CD73 can reduce the level of adenosine and reverse adenosine-mediated immune suppression. Therefore, CD73 has emerged as a valuable target for cancer immunotherapy. Here, a new series of malonic acid non-nucleoside derivatives were designed, synthesized and evaluated as CD73 inhibitors. Among them, compounds 18 and 19 exhibited significant inhibition activities against hCD73 with IC₅₀ values of 0.28 μM and 0.10 μM, respectively, suggesting the feasibility of replacing the benzotriazole moiety in the lead compound. This study explored the novelty and structural diversity of CD73 inhibitors.

Increased expression and activity of the PD-L1/PD-1 pathway suppresses the activation of cytotoxic T cells, which is vital in anti-tumour defence, allowing tumours to rise, expand and progress. Current strategies using antibodies to target PD-1/PD-L1 have been very effective in cancer therapeutics and companion diagnostics. Aptamers are a new class of molecules that offer an alternative to antibodies. Herein, the systematic evolution of ligands by exponential enrichment (SELEX) using agarose slurry beads was conducted to isolate DNA aptamers specific to recombinant human PD-L1 (rhPD-L1). Isolated aptamers were sequenced and analysed using MEGA X and structural features were examined using mFold. Three aptamer candidates (P33, P32, and P12) were selected for evaluation of binding affinity (dissociation constant, K_d) using ELONA and specificity and competitive inhibition assessment using the potentiostat-electrochemical method. Among those three, P32 displayed the highest specificity (8 nM) against PD-L1. However, P32 competes for the same binding site with the control antibody, 28–8. This study warrants further assessment of P32 aptamer as a potential, cost-effective alternative tool for targeting PD-L1.

Autophagy is a catabolic process that was described to play a critical role in advanced stages of cancer, wherein it maintains tumor cell homeostasis and growth by supplying nutrients. Autophagy is also described to support alternative cellular trafficking pathways, providing a non-canonical autophagy-dependent inflammatory cytokine secretion mechanism. Therefore, autophagy inhibitors have high potential in the treatment of cancer and acute inflammation. In our study, we identified compound 1 as an inhibitor of the ATG12-ATG3 protein–protein interaction. We focused on the systematic modification of the original hit 1, a casein kinase 2 (CK2) inhibitor, to find potent disruptors of ATG12-ATG3 protein–protein interaction. A systematic modification of the hit structure led us to a wide plethora of compounds that maintain its ATG12-ATG3 inhibitory activity, which could act as a viable starting point to design new compounds with diverse therapeutic applications.

Alzheimer’s disease is associated with a progressive loss of neurons and synaptic connections in the cholinergic system. Oxidative stress contributes to neuronal damages and to the development of amyloid plaques and neurofibrillary tangles. Therefore, antioxidants have been widely studied to mitigate the progression of Alzheimer’s disease, and among these, lipoic acid has demonstrated a neuroprotective effect. Here, we present the synthesis, the molecular modelling, and the evaluation of lipoic acid–donepezil hybrids based on O-desmethyldonepezil. As compounds 5 and 6 display a high inhibition of acetylcholinesterase (IC₅₀ = 7.6 nM and 9.1 nM, respectively), selective against butyrylcholinesterase, and a notable neuroprotective effect, slightly better than that of lipoic acid, the present study suggests that O-desmethyldonepezil could serve as a platform for the straightforward design of donepezil hybrids.

Regulatory T (Treg) cells play a central role in immune homeostasis. Forkhead box P3 (Foxp3), a hallmark molecule in Treg cells, is a vital transcription factor for their development and function. Studies have shown that degradation of the Foxp3 could provide therapeutic benefits in achieving effective anti-tumor immunity. In this study, we designed three PROTAC molecules, P60-L1-VHL, P60-L2-VHL, and P60-L3-VHL, based on a 15-mer peptide inhibitor of Foxp3 (P60), and explored their potential in regulating Foxp3 expression and function. Our data show that, among these molecules, P60-L3-VHL can inhibit the expression and nuclear localization of Foxp3 in HEK 293 T and HeLa cells, respectively. Meanwhile, use of proteasome inhibitor in P60-L3-VHL treated cells revealed an increased Foxp3 expression, indicating that P60-L3-VHL mediates the inhibition of Foxp3 through its degradation in the proteasome pathway. We further substantiate that P60-L3-VHL reduces the differentiation and Foxp3 expression in the in-vitro activated Treg cells. Overall, our findings suggest that P60-L3-VHL inhibits the differentiation of Treg cells by degrading the Foxp3, which may have potential implications in cancer immunotherapy.