Histone methyltransferases are involved in various biological functions, and these methylation regulating enzymes' abnormal expression or activity has been noted in several human cancers. Within this context, SET domain-containing (lysine methyltransferase) 7 (SET7, also called KMT7, SETD7, SET9) is of increasing significance due to its diverse roles in biological functions and diseases, such as diabetes, cancers, alopecia areata, atherosclerotic vascular disease, HIV, and HCV. In this study, DC-S100, which was discovered by pharmacophore- and docking-based virtual screening, was identified as the hit compound of SET7 inhibitor. Structure-activity relationship (SAR) analysis was performed on analogs of DC-S100 and according to the putative binding mode of DC-S100, structure modifications were made to improve its activity. Of note, compounds DC-S238 and DC-S239, with IC50 values of 4.88 and 4.59 μM, respectively, displayed selectivity for DNMT1, DOT1L, EZH2, NSD1, SETD8, and G9a. Taken together, DC-S238 and DC-S239 can serve as leads for further investigation as SET7 inhibitors and the chemical toolkits for functional biology studies of SET7.

Thymine DNA glycosylase (TDG) recognizes the geometry alteration of DNA minor grooves induced by 5-formylcytosine (5fC) in DNA demethylation pathways.

Chemical space exploration is a major task of the hit-finding process during the pursuit of novel chemical entities. Compared with other screening technologies, computational de novo design has become a popular approach to overcome the limitation of current chemical libraries. Here, we reported a de novo design platform named systemic evolutionary chemical space explorer (SECSE). The platform was conceptually inspired by fragment-based drug design, that miniaturized a “lego-building” process within the pocket of a certain target. The key to virtual hits generation was then turned into a computational search problem. To enhance search and optimization, human intelligence and deep learning were integrated. Application of SECSE against phosphoglycerate dehydrogenase (PHGDH), proved its potential in finding novel and diverse small molecules that are attractive starting points for further validation. This platform is open-sourced and the code is available at http://github.com/KeenThera/SECSE.

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Oncogenic mutations in critical nodes of cellular signaling pathways have been associated with tumorigenesis and progression. The B-Raf protein kinase, a key hub in the canonical MAPK signaling cascade, is mutated in a broad range of human cancers and especially in malignant melanoma. The most prevalent B-RafV600E mutant exhibits elevated kinase activity and results in constitutive activation of the MAPK pathway, thus making it a promising drug target for cancer therapy. Herein, we described the development of novel B-RafV600E selective inhibitors via multi-step virtual screening and hierarchical hit optimization. Nine hit compounds with low micromolar IC50 values were identified as B-RafV600E inhibitors through virtual screening. Subsequent scaffold-based analogue searching and medicinal chemistry efforts significantly improved both the inhibitor potency and oncogene selectivity. In particular, compounds 22f and 22q possess nanomolar IC50 values with selectivity for B-RafV600E in vitro and exclusive cytotoxicity against B-RafV600E harboring cancer cells.

A robust DNA-compatible Wittig reaction mediated by PPh2CH3 has been validated for DNA-conjugated α-chloroacetamides with aldehydes and, alternatively, DNA-conjugated aldehydes with α-halo acetamides or ketones. Further, 2-aminopyridines were acylated with α-chloroacetyl chloride and then reacted with DNA-conjugated aldehydes. Lastly, a pilot library employing our optimized Wittig reaction protocol was synthesized. The ability to generate α,β-unsaturated carbonyl compounds may be particularly useful for the design of DNA-encoded libraries capable of covalently interacting with protein targets.

Phosphoglycerate mutase 1 (PGAM1), an important enzyme in glycolysis, is overexpressed in a number of human cancers, thus has been proposed as a promising metabolic target for cancer treatments. The C-terminal portion of the available crystal structures of PGAM1 and its homologous proteins is partially disordered, as evidenced by weak electron density. In this study, we identified the conformational behavior of the C-terminal region of PGAM1 as well as its role during the catalytic cycle. Using the PONDR-FIT server, we demonstrated that the C-terminal region was intrinsically disordered. We applied the Monte Carlo (MC) method to explore the conformational space of the C-terminus and conducted a series of explicit-solvent molecular dynamics (MD) simulations, and revealed that the C-terminal region is inherently dynamic; large-scale conformational changes in the C-terminal segment led to the structural transition of PGAM1 from the closed state to the open state. Furthermore, the C-terminal segment influenced 2,3-bisphosphoglycerate (2,3-BPG) binding. The proposed swing model illustrated a critical role of the C-terminus in the catalytic cycle through the conformational changes. In conclusion, the C-terminal region induces large movements of PGAM1 from the closed state to the open state and influences cofactor binding during the catalytic cycle. This report describes the dynamic features of the C-terminal region in detail and should aid in design of novel and efficient inhibitors of PGAM1. A swing mechanism of the C-terminal region is proposed, to facilitate further studies of the catalytic mechanism and the physiological functions of its homologues.