Drug-Like Small Molecule HSP27 Functional Inhibitor Sensitizes Lung Cancer Cells to Gefitinib or Cisplatin by Inducing Altered Cross-Linked Hsp27 Dimers

Abstract

Relationships between heat shock protein 27 (HSP27) and cancer aggressiveness, metastasis, drug resistance, and poor patient outcomes in various cancer types including non-small cell lung cancer (NSCLC) were reported, and inhibition of HSP27 expression is suggested to be a possible strategy for cancer therapy. Unlike HSP90 or HSP70, HSP27 does not have an ATP-binding pocket, and no effective HSP27 inhibitors have been identified. Previously, NSCLC cancer cells were sensitized to radiation and chemotherapy when co-treated with small molecule HSP27 functional inhibitors such as zerumbone (ZER), SW15, and J2 that can induce abnormal cross-linked HSP27 dimer. In this study, cancer inhibition effects of NA49, a chromenone compound with better solubility, longer circulation time, and less toxicity than J2, were examined in combination with anticancer drugs such as cisplatin and gefitinib in NSCLC cell lines. When the cytotoxic drug cisplatin was treated in combination with NA49 in epidermal growth factor receptors (EGFRs) WT cell lines, sensitization was induced in an HSP27 expression-dependent manner. With gefitinib treatment, NA49 showed increased combination effects in both EGFR WT and Mut cell lines, also with HSP27 expression-dependent patterns. Moreover, NA49 induced sensitization in EGFR Mut cells with a secondary mutation of T790M when combined with gefitinib. Augmented tumor growth inhibition was shown with the combination of cisplatin or gefitinib and NA49 in nude mouse xenograft models. These results suggest the combination of HSP27 inhibitor NA49 and anticancer agents as a candidate for overcoming HSP27-mediated drug resistance in NSCLC patients.

Drug like HSP27 cross linkers with chromenone structure ameliorates pulmonary fibrosis

“…However, due to the inadequate solubility and short in vivo circulation time of J2, we have developed a more druggable compound, NA49 ( Figure 1A ). In comparison to J2, NA49 exhibited a superior pharmacokinetic profile and did not display any observable toxicity ( Yoo et al, 2021 ). NA49 induced HSP27 cross-linking and abnormal dimerization in L132 lung epithelial cells ( Figure 1B ).…”

“…Due to the limited solubility and short in vivo circulation time of J2, NA49 was developed as a more druggable compound. NA49 exhibits a superior pharmacokinetic profile compared to J2, showing improved characteristics such as enhanced bioavailability, longer circulation time, and negligible toxicity ( Yoo et al, 2021 ). Furthermore, the exposure to J2 at a concentration of 40 µg/plate for 48 h led to a significant increase in bacterial reverse mutation in the Ames test, utilizing Salmonella typhimurium strains TA98 and TA100, compared to the control vehicle group.…”

“…Previously, small molecule HSP27 inhibitors, such as ZER, SW15, and J2, have been shown to induce the formation of abnormal HSP27 dimers, were developed, and J2 showed inhibition of PF in various mouse models ( Kim et al, 2019 ; Yoo et al, 2021 ; Jeon et al, 2023 ). A drug’s chemical structure impacts its physicochemical properties of a drug are directly influenced by its chemical structure, and these properties, in turn, impact the drug’s ADME/Tox characteristics, ultimately determining its pharmacological effectiveness.…”

“…J2 ( Choi et al, 2017 ; Hwang et al, 2017 ) and NA49 ( Yoo et al, 2021 ) were chemically synthesized and previously described.…”

“…Some examples of these inhibitors include zerumbone, which was derived from a natural product, SW15, a synthetic xanthone compound ( Kim et al, 2016 ), and J2, a chromenone compound ( Choi et al, 2017 ; Hwang et al, 2017 ) However, these compounds faced the challenges in terms of their poor drugability or toxicity. Therefore, we developed NA49, a J2 derivative, which showed better drugability in absorption, distribution, metabolism, excretion, and toxicity (ADME/Tox) ( Yoo et al, 2021 ).…”