Obesity is closely associated with mitochondrial dysfunction, which impairs fatty acid oxidation and energy metabolism, yet currently available HDAC3 inhibitors have not been optimized to address these metabolic abnormalities. Herein, we developed a series of mitochondria-targeted HDAC3 inhibitors by incorporating a TPP moiety into the classical HDAC pharmacophore. Structure-based optimization identified H18 (IC50 = 45.4 nM) as the most promising candidate, exhibiting potent HDAC3 inhibitory activity together with preferential mitochondrial localization. H18 effectively suppressed lipid accumulation during 3T3-L1 adipocyte differentiation while restoring intracellular ATP levels and reducing oxidative stress. In diet-induced obese mice, H18 produced dose-dependent reductions in body weight gain, improved glucose tolerance, and insulin sensitivity and exhibited superior efficacy to BG45. Collectively, these findings identify H18 as a promising antiobesity lead compound and support the integration of mitochondrial targeting capability into HDAC3 inhibitor design as a promising strategy for obesity intervention.
Accurate and effective treatment of solid tumors has long been a core issue in cancer therapy. Antibody-drug conjugates (ADCs) represent a crucial breakthrough in precision oncology. Traditional ADCs rely on monoclonal antibodies generated through animal immunization, followed by screening, sequencing, and recombinant expressiona process that is experimentally complex and costly. In this study, we employed deep learning-based computational design methods to design mini-protein binders targeting the tumor-associated antigen TROP2. The designed TROP2 mini-protein binder exhibited high specificity and thermal stability. The binding affinity was optimized from 40.4 nM to 628 pM through partial diffusion. On this basis, we engineered the mini-protein binder by conjugating it with the microtubule inhibitor VcMMAE, thereby constructing mini-protein drug conjugates (MPDCs) that can specifically target and kill TROP2-positive tumor cells. A comprehensive assessment of the anti-tumor efficacy of these MPDCs was performed using cancer cell lines, organoid models, and mouse xenograft models.
Breakthrough hit-finding platforms rarely become routine after the first novel proof-of-concept and realistically take 20−30 years to develop fully. Across FBDD, DEL, Aptamer, and PROTAC drug discovery technologies, the persistent rate-limiting issue in platform development is not the founding concept alone (e.g., chemistry) rather, it is often more likely due to organizations underestimating the time to develop a robust technique in-house and the significant supporting infrastructure and talent required to transform novel technologies into routine hit-finding drug discovery platforms. A consequence for not being “all in” on its development can be a dilution of effort across programs that may lead to fewer clinical candidates and a decrease in ROI. As a result, it can take decades not years to develop a platform. Using lessons learned from these four platforms, this Perspective identifies key (and often unappreciated) hurdles that each new technology needs to resolve before becoming a mainstream hit-finding drug discovery platform driving FDA approvals.
Abstract G-Quadruplexes are non-canonical nucleic acid structures mostly located in gene promoters and telomeres. Although G4 stabilization with synthetic/natural ligands is a promising anticancer approach, dense distribution throughout the genome restricts their selective targeting. Additionally, cationic G4 ligands are widely used for good aqueous solubility and G-quadruplex binding, yet the charges reduce the ligand’s cellular permeabilization. In this work, the first example of a histone deacetylase-activatable G4 ligand, displaying a significant stabilization upon activation (26 °C, ΔTm), was developed. Having 1.8-fold more cellular uptake, the ligand increased G-quadruplexes in the cell almost 3-fold as verified by the G4-specific antibody. Oncogene expression including anti-apoptotic BCL-2 and telomerase was significantly suppressed, more selectively in HDAC2/HDAC6-overexpressing microsatellite unstable colon cancer, leading to a 73% decrease in proliferation. With a versatile chemical structure and a very large activity difference between ON and OFF states, the ligand has a promising therapeutic potential and can be a useful building block for the development of novel activatable G-quadruplex ligands.
Abstract Recurrence of infection is a challenge in treatment of Clostridioides difficile infection (CDI), observed in 25% of patients. The first-line antibiotics disturb the gut microbiota, exacerbating the already disrupted commensal gut homeostasis and allow for C. difficile colonization. Narrow-spectrum antibiotics are critical for selective targeting of C. difficile while preserving beneficial gut flora, thereby mitigating recurrence. Our study investigates a novel class of highly selective, nitroimidazole-based oxadiazole antibacterials. We detail the chemical basis for their exceptional selectivity against C. difficile over commensal bacteria and elucidate their mechanism of action. Oxadiazole 2 inhibits penicillin-binding proteins 1 and 3 involved in septal peptidoglycan biosynthesis during vegetative cell division. We further demonstrate by whole-genome sequencing that treatment of mice with oxadiazole 2 does not disrupt the gut microflora and confers an impediment to colonization by C. difficile. This work is foundational for development of a new generation of narrow-spectrum therapeutics to combat CDI.
