Clinical outcomes for previously treated patients with advanced biliary tract cancer - supplementary material

Supplemental Table 1: Search strategy for Embase (Embase 1974 to 2021 June 28)Supplemental Table 2: Search strategy for MEDLINE (Ovid MEDLINE In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily and Ovid MEDLINE(R) 1946 to June 28, 2021)Supplemental Table 3: Search strategy for CENTRAL (EBM Reviews - Cochrane Central Register of Controlled Trials May 2021)Supplemental Table 4: Search strategy for American Society of Clinical Oncology conference abstracts (Northern Light Life Sciences Conference Abstracts 2010 to 2021 Week 24)Supplemental Table 5: Search strategy for European Society for Medical Oncology conference abstracts (Northern Light Life Sciences Conference Abstracts 2010 to 2021 Week 24)Supplemental Table 6: Search strategy for ClinicalTrials.govSupplemental Table 7: Detailed study characteristics for trials included in the systematic reviewSupplemental Table 8: Detailed treatment characteristics for trials included in the systematic reviewSupplemental Table 9: Detailed patient characteristics for trials included in the systematic reviewSupplemental Table 10: Response outcomes for trials included in the systematic reviewSupplemental Table 11: Survival outcomes for trials included in the systematic reviewSupplemental Table 12: Safety outcomes for trials included in the systematic reviewSupplemental Table 13: Patient-reported outcomes for trials included in the systematic reviewSupplemental Table 14: Quality assessment of included single-arm and non-randomized trialsSupplemental Table 15: Summary of pooled KM estimates of OS Supplemental Table 16: Summary of KM estimates of PFS Supplemental Figure 1: Risk of bias assessment of included RCTs </p

Heat Shock Protein 70 Inhibitors. 1. 2,5′-Thiodipyrimidine and 5‑(Phenylthio)pyrimidine Acrylamides as Irreversible Binders to an Allosteric Site on Heat Shock Protein 70

Heat shock protein 70 (Hsp70) is an important emerging cancer target whose inhibition may affect multiple cancer-associated signaling pathways and, moreover, result in significant cancer cell apoptosis. Despite considerable interest from both academia and pharmaceutical companies in the discovery and development of druglike Hsp70 inhibitors, little success has been reported so far. Here we describe structure–activity relationship studies in the first rationally designed Hsp70 inhibitor class that binds to a novel allosteric pocket located in the N-terminal domain of the protein. These 2,5′-thiodipyrimidine and 5-(phenylthio)­pyrimidine acrylamides take advantage of an active cysteine embedded in the allosteric pocket to act as covalent protein modifiers upon binding. The study identifies derivatives <b>17a</b> and <b>20a</b>, which selectively bind to Hsp70 in cancer cells. Addition of high nanomolar to low micromolar concentrations of these inhibitors to cancer cells leads to a reduction in the steady-state levels of Hsp70-sheltered oncoproteins, an effect associated with inhibition of cancer cell growth and apoptosis. In summary, the described scaffolds represent a viable starting point for the development of druglike Hsp70 inhibitors as novel anticancer therapeutics