Exploration of Janus Kinase (JAK) and Histone Deacetylase (HDAC) Bispecific Inhibitors Based on the Moiety of Fedratinib for Treatment of Both Hematologic Malignancies and Solid Cancers.

The feedback activation of the Janus kinase (JAK)-STAT pathway leads to the fact that solid cancers are not sensitive to histone deacetylase (HDAC) inhibitors. Herein, a series of novel 2-amino-4-phenylaminopyrimidine JAK/HDAC dual-target inhibitors based on the moiety of fedratinib were designed and synthesized. Among them, 21 and 30 potently inhibited HDAC3/6 and JAK1/2 at nanomolar levels and exhibited splendid selectivity for the JAK2 against a panel of 76 kinases. 21 and 30 presented remarkable antiproliferative activity in both hematological malignancies and solid cancers, which was endorsed by JAK-STAT and HDAC pathway blockade and proapoptotic activity. On the basis of great plasma stability and oral bioavailability, 21 and 30 effectively suppressed the tumor growth of HEL and A549 xenograft models. Collectively, the above results validate that JAK/HDAC dual-target inhibitors provide valuable clues for targeted treatment of hematological malignancies and solid cancers.

Structure-based discovery of receptor tyrosine kinase AXL degraders with excellent anti-tumor activity by selectively degrading AXL and inducing methuosis.

The receptor tyrosine kinase (RTK) anexelekto (AXL) is mutated and/or overexpressed in various malignancies, and plays a central role in tumor development and acquired drug resistance. Although highly selective inhibitors have been developed in recent years, direct inhibition of AXL may block its ubiquitination, eventually leading to surface accumulation of the protein. Herein, we designed and synthesized a series of AXL degraders with high selectivity and without compensatory increase of AXL. In particular, compounds 20 and 22 showed significant AXL degradation capacity, which inhibited the proliferation and migration of cancer cells in vitro. In addition, these compounds induced the formation of cytoplasmic vacuoles and triggered methuosis, a new type of non-apoptotic cell death, by stimulating excessive production of macropinosomes. Vacuole formation was mediated via H-Ras activation, and was attenuated upon inhibition of its downstream regulatory factor Rac1. Furthermore, compound 20 inhibited the growth of tumor cell xenografts in vivo, and prolonged the survival of the tumor-bearing mice.

Emerging targeted protein degradation tools for innovative drug discovery: From classical PROTACs to the novel and beyond.

Targeted protein degradation technology has evolved a brand-new therapeutic modality from an innovative drug discovery perspective. Though the classical PROTACs has pioneered the way for protein degraders, certain inherent defects such as poor druggability, uncontrollable catalysis caused off-targets, and limited E3 ubiquitin ligases available constitute obstacles that impede further advances. Recent medicinal chemists have preferred to investigate a type of optimized degraders beyond the classical PROTACs, bypassing such disadvantages to better facilitate targeted protein degradation. In this perspective, we comprehensively spotlighted the emerging approaches and techniques applied to the targeted protein degradation, specifically the PROTACs-derived strategies and other alternatives to realize protein degradation via proteasome or lysosome. Besides, contemporary confronted opportunities as well as challenges were further analyzed, with the aim to guide future discovery of novel protein degraders.

A designed cyclic peptide based on Trastuzumab used to construct peptide-drug conjugates for its HER2-targeting ability.

Human epidermal growth factor receptor 2 (HER2) has been recognized as an important therapeutic target for its overexpression in many cancers. Trastuzumab is a monoclonal antibody targeting HER2, which has been approved by FDA to treat HER2-positive cancer. In this research, cyclic peptide Cyclo-GCGPep1 was designed based on the binding mode between antibody and HER2 protein in silico, which has been confirmed possessing good affinity with HER2. Cyclo-GCGPep1 was also used to construct peptide-drug conjugates with Camptothecin. Biological evaluations demonstrated that Conjugate 1 has a good antiproliferative activity on SK-BR-3 and NCI-N87 cells. Conjugate 1 retained the pro-apoptotic and Topo I inhibitory ability of Camptothecin. Meanwhile, it has good targeting ability towards HER2-positive cells with the help of Cyclo-GCGPep1. It also has better permeability in the tumor spheroid model than Camptothecin. In summary, the design of cyclic peptide derived from antibody is of significance for the discovery of targeting peptides and Conjugate 1 is expected as a good therapeutic agent for HER2-positive cancers.