br Introduction br Heat Shock Protein HSP
Heat Shock Protein 90 (HSP90), an ATP dependent molecular cha-perone, has been categorized as a crucial facilitator of oncogene addiction and cancer cell survival . A chaperone protein acts as a cellular machine responsible for correct folding and maturation of its client proteins and protects the cellular proteins from degradation by the ubiquitin-proteasome system in conditions of stress [2–7]. HSP90 has been shown to be over-expressed in solid and hematologic tumors which indicates that the con-tinued activity of HSP90 is required for oncogene-driven tumorigenesis. Thus inhibition of the chaperone function of HSP90 may lead to combi-natorial targeting of multiple oncogenic protein pathways and thus may overcome the notorious cancer resistance issue [7,8]. Over the years, Hsp90 inhibition has emerged as a fascinating chemotherapeutic strategy for the treatment of diverse malignancies [6,9–11]. The documented ac-tivity in this field supports the need to increase the number of investiga-tions on HSP90 inhibitors and this, in turn may escalate the probability of developing cancer therapeutics.
Although HSP90 as a therapeutic target for cancer has been ex-tensively validated using geldanamycin [12–14], the inclination of the medicinal chemist has shifted towards the design of second generation small molecule HSP90 inhibitors (Fig. 1). This could be attributed to
limitations such as poor bioavailability and hepatotoxicity that have hampered the clinical growth of ansamycin 3X FLAG Peptide . Resorcinol-based chemical architectures represent a prominent class of second generation HSP90 inhibitors [16–18]. Compounds such as AT-13387 (4), STA-9090 (5) and NVP-AUY922 (6) exemplify HSP90 inhibitors containing a resorcinol moiety . Despite the extensive efforts of the medicinal chemist towards the development of HSP90 inhibitors ex-erting anti-tumor effects in the last decade, clinical growth of these inhibitors was hampered/limited either by efficacy or adverse events in higher stage trials in addition to pharmaceutical property and com-mercialization issues [19–22]. As a result, none of the Hsp90 inhibitors are clinically approved yet. The termination of Phase III clinical trials of STA-9090 attributed to acquired resistance exemplifies a case where the clinical advancement of a HSP90 inhibitor was halted by moderate efficacy [19,23]. Overall, it can be concluded that despite the docu-mented promise in preclinical studies and early phase clinical trials, HSP 90 inhibitors have not been able to replicate the effectiveness at higher stage clinical investigations [6,20,24,25]. Experts have indicated that the clinical promise of HSP90 inhibition in cancer is likely to be improved with combination therapies and molecular stratification of patients . However, from the medicinal chemist’s perspective, the present scenario in HSP90 inhibitory field makes it quite prudent to
Corresponding author at: School of Pharmacy, College of Pharmacy, Taipei Medical University, Taiwan.
1 Contributed equally to this work.
Fig. 1. Chemical structures of HSP90 inhibitors.
expand the pipeline of rationally designed second generation HSP90 inhibitors as new cancer therapeutics. To accomplish this, the design of Hsp90 inhibitors via fusion of existing antitumor pharmacophores furnishing hybrid scaffolds as new chemotypes is anticipated to yield conclusive benefits of HSP90 inhibition in cancer. Other than this, the approach of dual balanced modulation of targets (having a biochemical correlation) may also be able to fully extract the anticancer potential of the chaperone function inhibition. Our ongoing drug discovery program is currently directed towards both these approaches; however this study solely employs the formerly mentioned strategy focused at the design and synthesis of new HSP90 inhibitors. Identification of key structural motifs and their appropriate fusion has emerged as a rational drug design strategy in recent years . The resorcinol fragment has been recognized as a crucial structural unit present in several second generation HSP90 inhibitors (4, 5, 6) (Fig. 1). Specifically, the 4-isopropyl resorcinol fragment serves as a key binder associated with the ATP binding site of HSP90 proteins by means of an appropriate fit in the hydrophilic and hydrophobic regions of the pro-tein [20,28,29]. This structural information led us direct our attempts towards the design of resorcinol bearing adducts as Hsp90 inhibitors. The other functionality selected for inclusion in the hybrid structure design was quinoline, a privileged heteroaryl scaffold in cancer drug discovery. The application of this bicyclic heterocycle has been fast spreading in medicinal chemistry owing to its remarkable biological and synthetic versatility [30–32]. Our recent investigations have com-prehensively explored quinoline-based anticancer scaffolds which exert antiproliferative effects via diverse mechanisms [33–35] and the results