Discovery of (2,4-Dihydroxy-5-isopropylphenyl)-[5-(4-methylpiperazin-1-ylmethyl)-1,3-dihydroisoindol-2-yl]methanone (AT13387), a Novel Inhibitor of the Molecular Chaperone Hsp90 by Fragment Based Drug Design

Woodhead, Andrew J.; Angove, Hayley C.; Carr, Maria G.; Chessari, Gianni; Congreve, Miles; Coyle, Joseph E.; Cosme, José; Graham, Brent; Day, Philip J.; Downham, Robert; Fazal, Lynsey; Feltell, Ruth E.; Figueroa, Eva; Frederickson, Martyn; Lewis, Jonathan J.; McMenamin, Rachel; Murray, Christopher W.; O’Brien, M. Alistair; Parra, Lina M.; Patel, Sahil; Phillips, Theresa R.; Rees, David C.; Rich, Sharna J.; Smith, Donna-Michelle; Trewartha, Gary; Vinković, Mladen; Williams, Brian H.; Woolford, Alison J.-A.

doi:10.1021/jm100060b

Cited by 237 publications

(178 citation statements)

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“…AT13387 is a novel small molecule inhibitor of HSP90 that was discovered with a fragment-based drug discovery approach that has been described in detail elsewhere. (32) X-ray crystallographic analysis of AT13387 in complex with the N-terminal domain of HSP90 showed that it bound within the N-terminal ATPase catalytic site and overlapped with the binding site for ATP. (32) Direct binding of AT13387 to HSP90 was investigated with isothermal calorimetry.…”

Section: Resultsmentioning

confidence: 99%

The heat shock protein 90 inhibitor, AT13387, displays a long duration of action in vitro and in vivo in non‐small cell lung cancer

Graham¹,

Curry²,

Smyth³

et al. 2012

Cancer Science

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A ubiquitously expressed chaperone, heat shock protein 90 (HSP90) is of considerable interest as an oncology target because tumor cells and oncogenic proteins are acutely dependent on its activity. AT13387 (2,4-dihydroxy-5-isopropyl-phenyl)-[5-(4-methyl-piperazin-1-ylmethyl)-1,3-dihydro-isoindol-2-yl] methanone, L-lactic acid salt) a novel, high-affinity HSP90 inhibitor, which is currently being clinically tested, has shown activity against a wide array of tumor cell lines, including lung cancer cell lines. This inhibitor has induced the degradation of specific HSP90 client proteins for up to 7 days in tumor cell lines in vitro. The primary driver of cell growth (mutant epidermal growth factor receptors) was particularly sensitive to HSP90 inhibition. The long duration of client protein knockdown and suppression of phospho-signaling seen in vitro after treatment with AT13387 was also apparent in vivo, with client proteins and phospho-signaling suppressed for up to 72 h in xenograft tumors after treatment with a single dose of AT13387. Pharmacokinetic analyses indicated that while AT13387 was rapidly cleared from blood, its retention in tumor xenografts was markedly extended, and it was efficacious in a range of xenograft models. AT13387's long duration of action enabled, in particular, its efficacious once weekly administration in human lung carcinoma xenografts. The use of longer-acting HSP90 inhibitors, such as AT13387, on less frequent dosing regimens has the potential to maintain antitumor efficacy as well as minimize systemic exposure and unwanted effects on normal tissues. (Cancer Sci 2012; 103: 522-527) T he super-chaperone system is involved in the folding and maturation of newly synthesized proteins.(1,2) HSP90 in particular aids in the folding and maturation of a distinct subset of proteins, which includes kinases, cell surface receptors and transcription factors. (3,4) The N-terminal domain ATPase activity of HSP90 is essential for this function.(5) Inhibition of this domain induces remodeling of the HSP90 chaperone complex, resulting in the recruitment of ubiquitin ligases, polyubiquitination and subsequent proteasomal degradation of HSP90 client proteins.(6,7) Through this mechanism, the inhibition of a single target enzyme can have a wide effect on the stability and, hence, the function of a large set of client proteins. As many oncogenic proteins are HSP90 clients, HSP90 inhibition has been found to have broad antitumor effects.(8-10) In contrast to more recent targeted therapies, where the appearance of new driver mutations or resistance mutations result in a loss of efficacy, client protein mutation increases dependence on HSP90 chaperoning activity as these mutations tend to render the proteins less stable. (11)(12)(13) Previous studies have also demonstrated that the constitutively activated mutant forms of EGFR are particularly dependent on HSP90 both in vitro and in vivo, (14)(15)(16) indicating an HSP90 inhibitor may be particularly efficacious in mutant EGFR tumors.After HSP90 inhibiti...

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Section: Resultsmentioning

confidence: 99%

The heat shock protein 90 inhibitor, AT13387, displays a long duration of action in vitro and in vivo in non‐small cell lung cancer

Graham¹,

Curry²,

Smyth³

et al. 2012

Cancer Science

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“…To date, there are 13 new Hsp90 inhibitors at various stages of clinical development (5)(6)(7)(9)(10)(11)(12)(13)(14)(15)(16)(17). The earlier geldanamycin analogues (i.e., 17-AAG or 17-DMAG), despite potent in vitro and in vivo preclinical activity, have not shown clear clinical benefit (5,31).…”

Section: Discussionmentioning

confidence: 99%

“…NVP-HSP990 is highly potent and selective for Hsp90 and represents one of the most potent oral Hsp90 inhibitors reported (5)(6)(7)(9)(10)(11)(12)(13)(14)(15)(16)(17). The GTL-16 model was selected as a screening model due to its growth and survival dependency on the Hsp90 client protein c-Met (24).…”

Section: Discussionmentioning

confidence: 99%

“…Currently, 13 synthetic Hsp90 inhibitors are under assessment in oncology clinical trials. Six inhibitors (IPI-504, NVP-AUY922, KW-2478, STA-9090, AT13387, and BIIB-028) are administered intravenously, whereas 7 (BIIB-021, IPI-493, XL-888, MPC-3100, DS-2248, Debio 0932, and NVP-HSP990) are dosed orally (5)(6)(7)(9)(10)(11)(12)(13)(14)(15)(16)(17). These inhibitors address some key pharmaceutical limitations of 17-AAG (5-7).…”

Section: Introductionmentioning

confidence: 99%

“…All other Hsp90 inhibitors are fully synthetic small molecules that fall into distinct structural classes including: (i) resorcinol-containing molecules (NVP-AUY922, KW-2478, STA-9090, and AT13387), (ii) purine scaffold (BIIB021, PU-H71, and MPC-3100), (iii) imidazopyridine (Debio 0932), (iv) 2-aminoterephthalamide (XL888), and (v) aminopyrimidine (NVP-HSP990). The chemical structures of BIIB028 and DS- 2248 have not yet been disclosed (5)(6)(7)(9)(10)(11)(12)(13)(14)(15)(16)(17).…”

Section: Introductionmentioning

confidence: 99%

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The Novel Oral Hsp90 Inhibitor NVP-HSP990 Exhibits Potent and Broad-spectrum Antitumor ActivitiesIn VitroandIn Vivo

Menezes

Taverna

Jensen

et al. 2012

Molecular Cancer Therapeutics

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A novel oral Hsp90 inhibitor, NVP-HSP990, has been developed and characterized in vitro and in vivo. In vitro, NVP-HSP990 exhibits single digit nanomolar IC 50 values on three of the Hsp90 isoforms (Hsp90a, Hsp90b, and GRP94) and 320 nanomolar IC 50 value on the fourth (TRAP-1), with selectivity against unrelated enzymes, receptors, and kinases. In c-Met amplified GTL-16 gastric tumor cells, NVP-HSP990 dissociated the Hsp90-p23 complex, depleted client protein c-Met, and induced Hsp70. NVP-HSP990 potently inhibited the growth of human cell lines and primary patient samples from a variety of tumor types. In vivo, NVP-HSP990 exhibits drug-like pharmaceutical and pharmacologic properties with high oral bioavailability. In the GTL-16 xenograft model, a single oral administration of 15 mg/kg of NVP-HSP990 induced sustained downregulation of c-Met and upregulation of Hsp70. In repeat dosing studies, NVP-HSP990 treatment resulted in tumor growth inhibition of GTL-16 and other human tumor xenograft models driven by well-defined oncogenic Hsp90 client proteins. On the basis of its pharmacologic profile and broad-spectrum antitumor activities, clinical trials have been initiated to evaluate NVP-HSP990 in advanced solid tumors.

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Structure‐Based Drug Design

Ferreira

Andricopulo

2021

Burger's Medicinal Chemistry and Drug Discovery

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Structure‐based drug design (SBDD) is the backbone of modern pharmaceutical research and development. Its origins date back to the 1950s and 1960s when the first X‐ray protein structures and pioneering studies correlating ligand–receptor binding and drug activity came out. With this foundation, seminal work on computer graphics enabled the first visualization and manipulation of virtual protein structures. These milestones opened the avenues for the growth of protein crystallography and molecular modeling, which thenceforth evolved side by side to culminate in modern SBDD. Today, SBDD can handle molecular targets previously regarded as intractable or undruggable, such as protein–protein interactions. Another advance coming from SBDD, fragment‐based drug discovery has excelled in optimizing weak ligands into drug‐like compounds. SBDD has provided groundbreaking drugs for many therapeutic areas, including highly complex conditions and diseases that were previously considered a death sentence. In fact, a substantial fraction of the drugs approved recently have been developed with the support of structural data. This article provides a perspective on the central aspects of this exciting field and explores the fundamentals of molecular modeling and its integration with X‐ray diffraction. The discussion of key concepts is followed by representative examples of the practice of SBDD.

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Discovery of (2,4-Dihydroxy-5-isopropylphenyl)-[5-(4-methylpiperazin-1-ylmethyl)-1,3-dihydroisoindol-2-yl]methanone (AT13387), a Novel Inhibitor of the Molecular Chaperone Hsp90 by Fragment Based Drug Design

Cited by 237 publications

References 62 publications

The heat shock protein 90 inhibitor, AT13387, displays a long duration of action in vitro and in vivo in non‐small cell lung cancer

The heat shock protein 90 inhibitor, AT13387, displays a long duration of action in vitro and in vivo in non‐small cell lung cancer

The Novel Oral Hsp90 Inhibitor NVP-HSP990 Exhibits Potent and Broad-spectrum Antitumor ActivitiesIn VitroandIn Vivo

Structure‐Based Drug Design

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