Design, synthesis and bioactivity evaluation of novel fusion peptides and their CPT conjugates inducing effective anti-tumor responses on HER2 positive tumors.

Human epidermal growth factor receptor 2 (HER2) represents an ideal target for antibody drug development, abnormal expression of the HER2 gene is associated with multiple tumor types. Pertuzumab, as the first monoclonal antibody inhibitor of HER2 dimerization, has been FDA-approved for HER2-positive patients. In order to enhance the activity of HER2-targeted peptide-drug conjugates (PDCs) developed based on pertuzumab, a novel class of conjugates 1-9 was designed and synthesized by fusing the N-terminal peptide sequence of the second mitochondria-derived activator of caspases (SMAC) with P1, followed by conjugation with CPT molecules. Compound 4 exhibited excellent in vitro anti-tumor activity across the three HER2-positive cell lines, comparable to the activity of CPT. Apoptosis induction assays indicated that the synergistic effect of the SMAC sequence enhanced the pro-apoptotic activity of the conjugate. Western Blot analysis and Caspase activity studies validated the mechanism through which SMAC peptides, in synergy with CPT, enhance the activity of PDCs. In vivo studies demonstrated that compound 4 possesses superior anti-tumor activity compared to CPT and can effectively mitigate potential renal toxicity associated with free SMAC peptides. In conclusion, conjugate 4 exhibited excellent anti-tumor activity both in vitro and in vivo, offering potential for further development as a novel peptide-conjugated drug.

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.

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.