Accumulation of missense mutant p53 (mutp53) in cancers promotes malignant progression. DNAJA1, a member of HSP40 (also known as J-domain proteins: JDPs), is shown to prevent misfolded or conformational mutp53 from proteasomal degradation. Given frequent addiction of cancers to oncogenic mutp53, depleting mutp53 by DNAJA1 inhibition is a promising approach for cancer therapy. However, there is no clinically available inhibitor for DNAJA1. Our in silico molecular docking study with a natural compound-derived small molecule library identified a plumbagin derivative, PLIHZ (plumbagin–isoniazid analog), as a potential compound binding to the J domain of DNAJA1. PLIHZ efficiently reduced the levels of DNAJA1 and several conformational mutp53 with minimal impact on DNA contact mutp53 and wild-type p53 (wtp53). An analog, called PLTFBH, which showed a similar activity to PLIHZ in reducing DNAJA1 and mutp53 levels, inhibited migration of cancer cells specifically carrying conformational mutp53, but not DNA contact mutp53, p53 null, and wtp53, which was attenuated by depletion of DNAJA1 or mutp53. Moreover, PLTFBH reduced levels of multiple other HSP40/JDPs with tyrosine 7 (Y7) and/or tyrosine 8 (Y8) but failed to deplete DNAJA1 mutants with alanine substitution of these amino acids. Our study suggests PLTFBH as a potential inhibitor for multiple HSP40/JDPs.

Epithelial‐to‐mesenchymal transition (EMT) is responsible for driving metastasis of multiple cancer types including lung cancer. Peroxisome proliferator‐activated receptor (PPAR)‐γ, a ligand‐activated transcription factor, controls expression of variety of genes involved in EMT. Although several synthetic compounds act as potent full agonists for PPAR‐γ, their long term application is restricted due to serious adverse effects. Therefore, partial agonists involving reduced and balanced PPAR‐γ activity are more effective and valued. A previous study discerned the efficacy of quercetin and its derivatives to attain favorable stabilization with PPAR‐γ. Here this work is extended by synthesizing five novel quercetin derivatives (QDs) namely thiosemicarbazone (QUETSC)) and hydrazones (quercetin isonicotinic acid hydrazone (QUEINH), quercetin nicotinic acid hydrazone (QUENH), quercetin 2‐furoic hydrazone (QUE2FH), and quercetin salicyl hydrazone (QUESH)) and their effects are analyzed in modulating EMT in lung cancer cell lines via PPAR‐γ partial activation. QDs‐treated A549 cells diminish cell proliferation strongly at nanomolar concentration compared to NCI‐H460 cells. Of the five screened derivatives, QUETSC, QUE2FH, and QUESH exhibit the property of partial activation as compared to the overexpressive level of rosiglitazone. Consistently, these QDs also suppress EMT process by markedly downregulating the levels of mesenchymal markers (Snail, Slug, and zinc finger E‐box binding homeobox 1) and concomitant upregulation of epithelial marker (E‐cadherin).

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The interaction of drugs with proteins plays a very important role in the distribution of the drug. Human serum albumin (HSA) is the most abundant protein in the human body and showing great binding characteristics has gained a lot of importance pharmaceutically. It plays an essential role in the pharmacokinetics of a number of drugs and hence several reports are available on the interaction of drugs with HSA. It can bind to cancer drugs and thus it is crucial to look at the binding characteristics of these drugs with HSA. Herein we summarize the binding properties of some anti-cancer drugs by specifically looking into the binding site with HSA. The number of drugs binding at Sudlow's site I situated in subdomain II A is more than the drugs binding at Sudlow's site II.

Epithelial-to-mesenchymal transition (EMT) is responsible for driving metastasis of multiple cancer types including lung cancer. Peroxisome proliferator-activated receptor (PPAR)-γ, a ligand-activated transcription factor, controls expression of variety of genes involved in EMT, cellular differentiation, fatty acid metabolism, insulin sensitivity and adipogenesis. Several synthetic compounds act as potent full agonist for PPAR-γ. However, owing to their serious adverse effects, restricts their long-term application. Therefore, partial agonist has been greatly in demand which involves reduced and balanced PPAR-γ activity. Our previous study discerned the efficacy of quercetin and its derivatives to attain favourable stabilization with PPAR-γ. Here we extended this work by synthesizing five novel quercetin derivatives (QDs) namely thiosemicarbazone (QUETSC) and hydrazones (QUEINH, QUENH, QUE2FH and QUESH) and analysed their effects in modulating EMT of lung cancer cell lines via PPAR-γ partial activation. QDs-treated A549 cells exhibited cell death strongly in a dose and time dependent manner at nanomolar concentration along with anti-migratory effects compared to NCI-H460 cells. Of the five derivatives we screened, QUETSC, QUE2FH and QUESH exhibited the property of partial activation as compared to the over-expressive level of rosiglitazone (RSG). Consistently, with PPAR-γ partial activation, these QDs also suppressed EMT process by markedly down-regulating the levels of mesenchymal markers (Snail, Slug and Zeb-1) and concomitant up-regulation of epithelial marker (E-cadherin). In the light of these evidences; QUETSC, QUE2FH and QUESH could be used as a novel selective partial PPAR-γ modulators whose pharmacological properties is distinct from RSG and may be exploited as potential therapeutic anti-metastatic agent.