Keywords: 2-Thioquinazoline-4-one, Anticancer activity, HSP90, Her2, HSP70, Apoptosis,
Molecular modeling.
1
. Introduction
The term ' Cancer ' itself is a kind of trauma to an enormous number of people due to the nature of
the disease. Among life-threatening diseases, cancer comes to the fore as the second most mortal
causing one-sixth of deaths worldwide [1]. Throughout recent years, the understanding and
treatment of cancer has progressed rapidly, which is reflected in terms of several clinically
approved blockbuster drugs [2, 3]. However, heterogeneity and inherent drug resistance ability of
cancer cells pose a significant obstacle for cancer therapy. Thus, enormous amount of efforts were
conducted to identify the molecular targets that can simultaneously affect multiple oncoproteins
and their signaling pathways in order to effectively combat cancer [4]. Heat shock proteins (HSPs)
play an important role in this regard. Heat shock protein 90 (HSP90) is a constitutively expressed
ATP dependent chaperone that plays a central role in assembly, folding, trafficking, and
degradation processes of various client proteins, many of them are oncogenic proteins which
involved in pathways of cell proliferation, angiogenesis, invasion and metastasis, and contribute
to all six hallmarks of cancer [5, 6]. Thus, inhibition of HSP90 would result in degradation of the
client proteins and suppress the growth and proliferation of cancer cells. Further therapeutic
potential of HSP90 is enhanced by the fact that it is overexpressed 2-10 fold higher in cancer cells
than that in normal healthy cells [7]. Besides, targeting HSP90 can overcome the notorious cancer
resistance issue due to its potential for combinatorial targeting of multiple oncogenic protein
pathways [8]. Therefore, HSP90 has emerged as an ideal and selective new target for anticancer
therapy and development of HSP90 inhibitors has become one of the leading areas of research in
recent drug discovery and development.
Over the past decades, a number of HSP90 inhibitors have been reported. The first generation of
HSP90 inhibitors were derived from natural products such as Geldanamycin (I) and Radicicol (II)
[9]. Modification of Geldanamycin led to the identification of Tanespimycin (17-AAG) (III),
which was the first HSP90 inhibitor entered into clinical trials in 1999 [10]. The following studies
developed various totally synthesized small molecule inhibitors with scaffolds of various kinds as
the second generation of HSP90 inhibitors [11, 12]. To date, there are approximately twenty
HSP90 inhibitors that have been entered into clinical trials. Unfortunately, no HSP90 inhibitors
2