Synthesis of Anti-Pancreatic Cancer Natural Product Majusculamide D and Analogues Reveals a Preliminary Structure-Activity Relationships

The total synthesis of majusculamide D(1)was achieved from commercially available materials.In addition,we synthesized eight analogues including three stereoisomers of majusculamide D that differ in the fatty acid chain.Six analogues including a simplified analogue 29 exhibited significant nanomolar-level IC50 values against Panc-1 cells in MTT assays.A preliminary SAR analysis indicated that the hydroxyl group at C10 and C2−C3 unsaturated double bond of majusculamide D were essential in maintaining the high activity against Panc-1 cells and the orientation of C40-Me and C42-Me groups was tolerable.

Molecular glue triggers degradation of PHGDH by enhancing the interaction between DDB1 and PHGDH

Cancer stem cells(CSCs)play a pivotal role in tumor initiation,proliferation,metastasis,drug resistance,and recurrence.Consequently,targeting CSCs has emerged as a promising avenue for cancer therapy.Recently,3-phosphoglycerate dehydrogenase(PHGDH)has been identified as being intricately associated with the regulation of numerous cancer stem cells.Yet,reports detailing the functional regulators of PHGDH that can mitigate the stemness across cancer types are limited.In this study,the novel“molecular glue”LXH-3-71 was identified,and it robustly induced degradation of PHGDH,thereby modulating the stemness of colorectal cancer cells(CRCs)both in vitro and in vivo.Remarkably,LXH-3-71 was observed to form a dynamic chimera,between PHGDH and the DDB1-CRL E3 ligase.These insights not only elucidate the anti-CSCs mechanism of the lead compound but also suggest that degradation of PHGDH may be a more viable therapeutic strategy than the development of PHGDH inhibitors.Additionally,compound LXH-3-71 was leveraged as a novel ligand for the DDB1-CRL E3 ligase,facilitating the development of new PROTAC molecules targeting EGFR and CDK4 degradation.

Ca^(2+)-calpains axis regulates Yki stability and activity in Drosophila

Yorkie(Yki)is a key effector of the Hippo pathway that activates the expression of targets by associating with the transcription factor Scalloped.Various upstream signals,such as cell polarity and mechanical cues,control transcriptional programs by regulating Yki activity.Searching for Yki regulatory factors has far-reaching significance for studying the Hippo pathway in development and human diseases.In this study,we identify Calpain-A(CalpA)and Calpain-B(CalpB),two calcium(Ca^(2+))-dependent modulatory proteases of the calpain family,as critical regulators of Yki in Drosophila that interact with Yki,respectively.Ca?+induces Yki cleavage in a CalpA/CalpB-dependent manner,and the protease activity of CalpA/CalpB is pivotal for the cleavage.Furthermore,overexpression of CalpA or CalpB in Drosophila partially restores the large wing phenotype caused by Yki overexpression,and F98 of Yki is an important cleavage site by the Ca^(2+)-calpains axis.Our study uncovers a unique mechanism whereby the Ca^(2+)-calpain axis modulates Yki activity throughprotein cleavage.