Minhang Xin

Proteolysis-targeting chimera (PROTAC) technology was employed to achieve the degradation of PI3Kδ in this study, and a series of PROTAC-based PI3Kδ degraders were first developed. Lysine-targeted covalent strategy led to the discovery of novel potent PROTAC-based PI3Kδ degraders. After screening and structure-activity relationship study, B14 was optimal and exhibited strong antiproliferation and selective PI3Kδ inhibition, with a high degradation value (DC₅₀ = 3.98 nM). B14 induced cell cycle arrest in the premitotic phase and prompted cell apoptosis. B14 displayed effective suppression of the tumor growth in the xenograft model and significantly promoted the PI3Kδ degradation in vivo. Most importantly, B14 bound to the Lys779 of PI3Kδ to selectively degrade PI3Kδ by covalent-bonding. Mechanistic studies indicated that the ubiquitin-proteasome pathway was involved in the degradation process. This study provided an effective approach for developing PROTAC-based PI3Kδ degraders, and the lysine-targeted covalent strategy laid the foundation for the further design of potent PI3Kδ-targeting PROTACs.

Targeting the lysine residue of protein kinases to develop covalent inhibitors is an emerging hotspot. Herein, we have reported an approach to develop lysine-targeted covalent inhibitors of PI3Kδ by in situ interaction upgradation of the H-bonding to covalent bonding. Several warhead groups were introduced and screened in situ, leading to lysine-targeted covalent inhibitors bearing aromatic esters with high bioactivity and PI3Kδ selectivity. Compound A11 bearing phenolic ester was finally optimized to show a long duration of action in SU-DHL-6 cells by multiple assays. Docking simulation and further protein mass spectrometry confirmed that A11 bound to PI3Kδ by covalent-bonding interactions with Lys779. Furthermore, A11 exhibited potently antitumor efficacy without obvious toxicity in the SU-DHL-6 and Pfeiffer xenograft mouse models. This study identified A11 to be a much more effective antitumor agent in vitro and in vivo as a lysine-targeted covalent inhibitor, and it also provided a practical approach for the development of lysine-targeted covalent inhibitors.

The delta isoform of class I PI3K (PI3K delta) has been shown as a promising target for the treatment of hematologic malignancies and immune diseases. Herein, a series of pyrido[3,2-d]pyrimidine derivatives were designed, synthesized and evaluated for the preliminary bioactivity. Compared with idelalisib, compound S5 exhibited excellent enzyme activity against PI3K delta (IC50 = 2.82 nM) and strong antiproliferation activity against SU-DHL-6 cells (IC50 = 0.035 mu M). Besides, S5 inhibited the phosphorylation of Akt, which is downstream of PI3K delta, in concentrationdependent manner. In view of the significant improvement in potency of PI3K delta and selectivity over other PI3K isoforms, Compound S5 deserved further investigation as a promising PI3K delta inhibitor.

Aim: In our study compounds with pyrido[3,2-d]pyrimidine and pyrido[3,4-d]pyrimidine were designed, synthesized and evaluated for their biological activity against hematologic tumors. Methods: The ... Graphical abstract

Recent years have witnessed the rapid development of targeted protein degradation (TPD), especially proteolysis targeting chimeras. These degraders have manifested many advantages over small molecule inhibitors. To date, a huge number of degraders have been excavated against over 70 disease‐related targets. In particular, degraders against estrogen receptor and androgen receptor have crowded into phase II clinical trial. TPD technologies largely expand the scope of druggable targets, and provide powerful tools for addressing intractable problems that can not be tackled by traditional small molecule inhibitors. In this review, we mainly focus on the structures and biological activities of small molecule degraders as well as the elucidation of mechanisms of emerging TPD technologies. We also propose the challenges that exist in the TPD field at present.

Introduction of the N,N-dimethylaminoethoxy group to pyrido[3,2-d]pyrimidine led to the discovery of menin-mixed lineage leukemia (MLL) interaction inhibitor C20. C20 showed strong binding affinity to menin protein and achieved sub-micromolar potency in cell growth inhibition. C20 had good selectivity for the inhibition of the interaction between menin and MLL in the kinase profile evaluation. Pharmacokinetic studies demonstrated that C20 possessed good stability and low clearance rate in liver microsomes and acceptable bioavailability in rats. Subsequent oral administration of C20 showed potent antitumor activity in the MV4;11 subcutaneous xenograft models of MLL-rearranged leukemia. The docking study showed that C20 bound highly with menin, and the N,N-dimethylaminoethoxy group occupied the F9 pocket of menin. This study proved that introducing a hydrophilic group into the F9 pocket of menin would be a new strategy for the design of menin-MLL interaction inhibitors with potent binding affinity and improved physical properties.