Targeting the entry region of Hsp90's ATP binding pocket with a novel 6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl amide

2018

Oncol Rep

Triple-negative breast cancers (TNBCs) are the most aggressive and metastatic subtype of breast cancers and exhibit poor clinical outcome due to the lack of drug target receptors such as estrogen receptors (ER), progesterone receptors (PR), and human epidermal growth factor receptor 2 (Her2). The limited effectiveness of therapeutic options and the poor prognosis of TNBC patients emphasize the urgent need for identifying new therapeutic agents. In this regard, heat shock protein 90 (Hsp90) has emerged as a promising therapeutic target for the treatment of TNBCs. Hsp90 is a molecular chaperone that regulates the folding, stability, and function of many oncogenic proteins. Hence, the inhibition of Hsp90 chaperone function leads to a simultaneous blockage of multiple signaling pathways in the proliferation and survival of cancers. In the present study, we performed the design, synthesis, and biological evaluation of Hsp90 inhibitors and found that a synthetic small molecule, DPide exerted a potent anticancer activity against TNBC cell line, MDA‑MB‑231 and non‑small cell lung cancer (NSCLC) cell line, H1975 with GI50 values of 0.478 and 1.67 µM, respectively. Soft‑agar colony formation assay also revealed that DPide suppressed the anchorage‑independent growth of MDA‑MB‑231 cells. Western blot analysis indicated that the treatment of MDA‑MB‑231 cells with DPide induced the proteasomal degradation of EGFR, Her2, Met, Akt, c‑Raf, and Cdk4 and the consequent cleavage of PARP, leading to apoptotic cell death. DPide also inhibited the migration and MMP9 activity of MDA‑MB‑231 cells, suggesting that the metastatic potential of TNBCs could be suppressed by DPide. Collectively, DPide offers an effective therapeutic option for the treatment TNBCs.

Section: Resultsmentioning

confidence: 92%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The targeted inhibition of Hsp90 by a synthetic small molecule, DPide offers an effective treatment strategy against TNBCs

Park

2018

Oncol Rep

“…In this regard, HSP90 inhibitors have been extensively studied. We have also reported several novel HSP90 inhibitors based on resorcinol and 1,3,5-triazines [ 4 , 5 , 6 , 7 ]. Several HSP90 inhibitors are currently tested in clinical trials [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

Small Molecule Inhibitors of HSF1-Activated Pathways as Potential Next-Generation Anticancer Therapeutics

Sharma

2018

Molecules

Targeted therapy is an emerging paradigm in the development of next-generation anticancer drugs. Heat shock factor 1 (HSF1) has been identified as a promising drug target because it regulates several pathways responsible for cancer cell growth, metastasis, and survival. Studies have clearly demonstrated that HSF1 is an effective drug target. Herein, we provide a concise yet comprehensive and integrated overview of progress in developing small molecule inhibitors of HSF1 as next-generation anticancer chemotherapeutics while critically evaluating their potential and challenges. We believe that this review will provide a better understanding of important concepts helpful for outlining the strategy to develop new chemotherapeutic agents with promising anticancer activities by targeting HSF1.

“…In our ongoing effort to develop a new Hsp90 inhibitor (22)(23)(24)(25)(26), we have recently found that a chalcone-based small molecule (E)-3-(2-bromo-3,4,5-trimethoxyphenyl)-1-(2,4-dihydroxyphenyl)prop-2-en-1-one (BDP) impairs the growth of cancer cells and this observation prompted us to direct our efforts toward investigating its biological activities and the underlying mechanisms of action.…”

Section: Introductionmentioning

confidence: 99%

A novel chalcone-based molecule, BDP inhibits MDA-MB-231 triple-negative breast cancer cell growth by suppressing Hsp90 function

2017

Oncology Reports

Self Cite

Triple-negative breast cancer (TNBC) is a molecularly diverse and heterogeneous disease and the molecular heterogeneity of TNBC increases the difficulty in improving survival rates. To date, therapeutic approaches for the treatment of TNBC such as hormonal chemotherapy and trastuzumab-based therapy have been limited by the lack of target receptors such as estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (Her2), emphasizing the urgent need for identifying new therapeutic options. In this regard, heat shock protein 90 (Hsp90) has emerged as an attractive therapeutic target for TNBC. Hsp90 plays a central role in regulating correct folding, stability, and function of numerous oncogenic proteins. In the present study, we evaluated the in vitro effect of a small molecule Hsp90 inhibitor, (E)-3-(2-bromo-3,4,5-trimethoxyphenyl)-1-(2,4-dihydroxyphenyl)prop-2-en-1-one (BDP) on TNBC cell line, MDA‑MB‑231. This study indicated that BDP efficiently inhibited the growth of MDA‑MB‑231 cells in a dose- and time-dependent manner. BDP induced overall degradation of multiple oncogenic proteins including EGFR, Her2, Met, Akt, c‑Raf, and Cdk4, consequently leading to apoptotic cell death. The flow cytometric analysis revealed that BDP promoted cell cycle arrest at G2/M phases. Moreover, BDP treatment attenuated the migration of MDA‑MB‑231 cells and impaired MMP9 activity, which are essential processes for tumor metastasis. Collectively, BDP represents a new class of Hsp90 inhibitor and shows therapeutic potential for TNBC treatment.