Fatty acid conjugated BimBH3 analogues with d‑amino acid substitution as PTPN1 inhibitors with enhanced activity, biostability and orally available potency for the treatment of diabetes.

Protein tyrosine phosphatase non-receptor type 1 (PTPN1) is a crucial regulator of insulin and leptin signaling pathways, positioning it as a promising therapeutic target for the development of insulin sensitizers in the treatment of type 2 diabetes mellitus (T2DM). Our previous studies demonstrated that lipidated/acylated BimBH3 core peptide analogues function as potent PTPN1 inhibitors with potential for once-weekly hypoglycemic efficacy. Additionally, alanine scanning identified specific residues that could be modified without compromising inhibitory activity.

Site-Specifically Modified Peptide Inhibitors of Protein Tyrosine Phosphatase 1B and T-Cell Protein Tyrosine Phosphatase with Enhanced Stability and Improved In Vivo Long-Acting Activity.

Protein tyrosine phosphatase 1B (PTP1B) and TC-PTP can function in a coordinated manner to regulate diverse biological processes including insulin and leptin signaling, T-cell activation, and tumor antigen presentation, which makes them potential targets for several therapeutic applications. We have previously demonstrated that the lipidated BimBH3 peptide analogues were a new class of promising PTP1B inhibitors with once-weekly antidiabetic potency. Herein, we chemically synthesized two series of BimBH3 analogues via site-specific modification and studied their structure-activity relationship.

Methylation of Septin9, SRSF1, and PAX8 in Early Screening of Colorectal Cancer in the Population Undergoing Physical Examinations.

Background: The aim was to investigate the value of blood Septin9, SRSF1, and PAX8 gene methylation detection techniques in early screening of colorectal cancer (CRC).

Methods: A prospective cohort study enrolled 3,000 participants undergoing routine physical examination at Shizong County People's Hospital Health Management Center from December 2021 through November 2022, including 1,512 males and 1,488 females, ranging in age from 20 to 90 years, with a median age of 49 years. Fresh blood samples were collected and tested for Septin9, SRSF1, and PAX8 gene methylation.

Discovery of Novel PTP1B Inhibitors with Once-Weekly Therapeutic Potential for Type 2 Diabetes: Design, Synthesis, and and Investigations of BimBH3 Peptide Analogues.

Poor medication adherence in patients with type 2 diabetes mellitus has become one of the main causes of suboptimal glycemic control. Once-weekly drugs can markedly improve the convenience, adherence, and quality of life of T2DM patients; thus, they are clinically needed and preferred. PTP1B plays a negative role in both insulin and leptin signaling pathways, which makes it an important target for diabetes.