康龙化成（股票代码：300759.SZ/3759.HK）是国际领先的生命科学研发服务企业。自2004年成立以来，康龙化成一直致力于其人才培养和设施建设，为包括小分子、大分子和细胞与基因治疗药物在内的多疗法药物研发打造了一个贯穿药物发现，临床前及临床开发全流程的研发生产服务体系。康龙化成在中国、美国、英国均开展运营，拥有14,000多名员工，向北美、欧洲、日本和中国的合作伙伴提供研发解决方案并与之保持良好的合作关系。
Dithiocarbamates (DTCs) are privileged scaffolds in medicinal chemistry, yet inaccessible via DNA-encoded libraries (DELs) due to a lack of robust on-DNA synthesis. We developed a general procedure for on-DNA DTC formation using a carbon disulfide (CS2) bridging strategy. This method efficiently links diverse aliphatic secondary amines and alkyl halides under mild conditions with high conversions and excellent DNA compatibility. The utility of this method was demonstrated by constructing a prototype DEL, thereby bridging a critical gap in chemical space and facilitating the rapid discovery of DTC-based therapeutics.
Creatine, a naturally occurring guanidine carboxylic acid, serves as a critical energy metabolite in tissues with high energy demands. Certain cancers upregulate creatine metabolism to supplement their energy needs. Ompenaclid, a salt form of the well-studied creatine transporter inhibitor 3-guanidinopropionic acid (β-GPA), is in clinical development for the treatment of patients with colorectal tumors. Existing SLC6A8 inhibitors are low-potency molecules and frequently interact with related transporters. Herein, we report the discovery of SLC6A8 inhibitors with increased selectivity as well as in vitro and in vivo potency. A bioisostere approach was used by replacing the carboxylic acid of β-GPA with surrogate functional groups to achieve these improvements. Docking of these inhibitors into the recently published SLC6A8 cryo-EM structure reveals key binding contacts and supports the observed structure-activity relationships.
Ecopipam is a dopamine-1 (D1) receptor antagonist in development for Tourette syndrome. In vitro data showed that ecopipam is metabolized to ecopipam glucuronide through uridine diphosphate-glucuronosyltransferase 1A9 and to EBS-101-40853 (previously called N-desmethylecopipam or SCH 40853) through cytochrome P450 3A4. This open-label, non-randomized, mass balance study investigated metabolism and elimination pathways of ecopipam. A single oral dose of ecopipam 179.2 mg containing 88.5 μCi (3.27 MBq) of [14C]-labeled ecopipam was administered to 8 healthy males. Total radioactivity, ecopipam, and ecopipam metabolite concentrations were measured in blood, plasma, urine, and feces periodically until discharge (between Days 8 and 15 postdose). Pooled plasma was used to identify and quantify unknown metabolites. Overall, 83.3% of radioactivity was recovered in urine as metabolites (< 1% as ecopipam), and 8.27% was excreted in feces (6.43% as ecopipam). Ecopipam glucuronide accounted for 80.0% of radioactivity in plasma and 66.9% of radioactivity in urine. EBS-101-40853 accounted for 10.5% of the plasma AUC∞ for ecopipam. Geometric mean half-lives of ecopipam, EBS-101-40853, and total radioactivity in plasma were 17.3, 25.6, and 94.1 h, respectively. Uncharacterized metabolites P3 and P5, 'corrected' for extraction efficiency, had plasma half-lives (97.4 and 122 h, respectively) similar to total radioactivity. Unknown P3, P4, and P5 metabolites accounted for 4.62%, 0.243%, and 6.03%, respectively, of plasma radioactivity. Ecopipam is primarily metabolized to ecopipam glucuronide, with only 10.5% metabolized to EBS-101-40853. The long half-life of plasma radioactivity was attributed to previously uncharacterized metabolites that each accounted for < 10% of radioactivity and were considered not clinically relevant.
RLY-2139 is a potent and selective orthosteric CDK2/Cyclin E inhibitor in development for the treatment of ER+/HER2- breast cancer. It showed an on target IC50 of 4 nM for CDK2/CycE and good biochemical selectivity, e.g., 100x for CDK1/CycB, 320x for CDK6/CycD3, and 2400x for CDK9/CycT1. We report the route optimization and scale-up of a robust, cGMP-compliant synthesis for RLY-2139 to support preclinical and early clinical supply. The convergent route couples two advanced intermediates 1 and 2 followed by deprotections and functional group transformations to deliver the drug substance. Key optimizations included replacing T3P with CMPI to address operational constraints, substituting HFTEA with aqueous TBAF to improve safety, and employing N,N '-disuccinimidyl carbonate (DSC) in place of phenyl chloroformate to eliminate phenolic byproducts and enable telescoping. Rearranging late-stage steps improved impurity control and process robustness, while scalable recrystallization replaced column chromatography. The optimized sequence was successfully demonstrated on multi-kilogram scale, delivering 14.7 kg of crystalline RLY-2139 (67% overall yield from 1) with >99.9% chemical purity (LCAP) and 100% chiral purity.
Generative artificial intelligence (AI) is now widely applied in medicinal chemistry, with detailed case studies emerging in the literature. Here, we describe an early application of REINVENT, AstraZeneca's in-house generative molecular design platform, to identify new inhibitor scaffolds for hematopoietic progenitor kinase 1 (HPK1). REINVENT was deployed at two stages of the project to address distinct design objectives. For hit identification, transfer learning on kinase-active compounds, followed by reinforcement learning guided by QSAR-based scoring, led to the discovery of three active chemotypes. Subsequently, REINVENT was applied to scaffold hopping, using 3D pharmacophore and docking models as scoring functions, which enabled the identification of two additional active chemotypes. Optimization of one of these scaffolds delivered a compound with potent cellular activity, kinase selectivity, and favorable rat pharmacokinetics. These results demonstrate the value of integrating generative AI with medicinal chemistry expertise and support broader application of the approach in future discovery programs.
