Discovery of XL888: A novel tropane-derived small molecule inhibitor of HSP90

Bussenius, Joerg; Blazey, Charles M.; Aay, Naing; Anand, Neel K.; Arcalas, Arlyn; Baik, TaeGon; Bowles, Owen J.; Buhr, Chris A.; Costanzo, Simona; Curtis, Jeffrey K.; DeFina, Steven C.; Dubenko, L. G.; Heuer, Timothy S.; Huang, Ping; Jaeger, Christopher T.; Joshi, Anagha A; Kennedy, Abigail R.; Kim, Angie I.; Lara, Katherine K.; Lee, Jae; Li, Jonathan; Lougheed, Julie C.; Ma, Sunghoon; Malek, Shiva; Manalo, Jean-Claire L.; Martini, Jean-François; McGrath, Garth; Nicoll, Monique; Nuss, John M.; Pack, Michael; Peto, Csaba; Tsang, Tsze H.; Wang, Longcheng; Womble, Scott; Yakes, Michael; Zhang, Wentao; Rice, Kenneth D.

doi:10.1016/j.bmcl.2012.07.052

Cited by 66 publications

(26 citation statements)

References 32 publications

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“…In parallel, a different group separately identified a tropane from a high-throughput screen of 4.1 million compounds 40 , and ultimately advanced this to a derivative yielding tumor regression in a mouse xenograft model. There is structural similarity between this HTS hit and the previous fragment hit, and indeed this ring once again binds at the location of ADP’s adenine moiety.…”

Section: Discussionmentioning

confidence: 99%

When Does Chemical Elaboration Induce a Ligand To Change Its Binding Mode?

Malhotra

Karanicolas

2016

J. Med. Chem.

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Traditional hit-to-lead optimization assumes that upon elaboration of chemical structure, the ligand retains its binding mode relative to the receptor. Here, we build a large-scale collection of related ligand pairs solved in complex with the same protein partner: we find that for 41 of 297 pairs (14%), the binding mode changes upon elaboration of the smaller ligand. While certain ligand physiochemical properties predispose changes in binding mode, particularly those properties that define fragments, simple structure-based modeling proves far more effective for identifying substitutions that alter the binding mode. Some ligand pairs change binding mode because the added substituent would irreconcilably conflict with the receptor in the original pose, whereas others change because the added substituent enables new, stronger interactions that are available only in a different pose. Scaffolds that can engage their target using alternate poses may enable productive structure-based optimization along multiple divergent pathways.

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Section: Discussionmentioning

confidence: 99%

When Does Chemical Elaboration Induce a Ligand To Change Its Binding Mode?

Malhotra

Karanicolas

2016

J. Med. Chem.

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“…To demonstrate the capability of our method to provide quantification of drug specific changes in Hsp90 structure, we targeted selected cross-linked peptide pairs identified from the 17-AAG dataset in cells treated with two additional Hsp90 inhibitors, namely the NTD binding, ATP-competitive inhibitor XL888 (Bussenius et al, 2012) and the CTD binding inhibitor Novobiocin(Marcu et al, 2000; Matts et al, 2011). As illustrated in Fig.…”

Section: Resultsmentioning

confidence: 99%

In Vivo Conformational Dynamics of Hsp90 and Its Interactors

Chavez

Schweppe

Eng

et al. 2016

Cell Chemical Biology

133

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Summary Hsp90 belongs to a family of some of the most highly expressed heat shock proteins that function as molecular chaperones to protect the proteome not only from the heat shock, but from other misfolding events. As many client proteins of Hsp90 are involved in oncogenesis, this chaperone has been in focus of intense research efforts. Yet, we lack structural information for how Hsp90 interacts with co-chaperones and client proteins. Here, we develop a mass spectrometry based approach that allows quantitative measurements of in vitro and in vivo effects of small molecule inhibitors on Hsp90 conformation, and interaction with co-chaperones and client proteins. From this analysis we were able to derive structural models for how Hsp90 engages its interaction partners in vivo and how different drugs affect these structures. Additionally, the methodology described here offers a new approach to probe the effects of virtually any inhibitor treatment on the proteome level.

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“…First, the initial hits were found via an HTS campaign of 4.1 million compounds using an in-house chemical library [83]. The challenges encountered during the structure-based approach used for their optimization efforts pertained to reducing the high molecular weights (> 650 amu) and polar surface areas (> 135 Å 2 ), which were outside the ideal range for orally bioavailable drugs [83]. …”

Section: Hsp90 Clinical Agents: Second Generationmentioning

confidence: 99%

Heat shock protein 90 inhibitors in the treatment of cancer: current status and future directions

Jhaveri

Ochiana

Dunphy

et al. 2014

Expert Opinion on Investigational Drugs

156

173

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Introduction Heat shock protein 90 (HSP90) serves as a critical facilitator for oncogene addiction. There has been augmenting enthusiasm in pursuing HSP90 as an anticancer strategy. In fact, since the initial serendipitous discovery that geldanamycin (GM) inhibits HSP90, the field has rapidly moved from proof-of-concept clinical studies with GM derivatives to novel second-generation inhibitors. Areas covered The authors highlight the current status of the second-generation HSP90 inhibitors in clinical development. Herein, the authors note the lessons learned from the completed clinical trials of first- and second-generation inhibitors and describe various assays attempting to serve for a more rational implementation of these agents to cancer treatment. Finally, the authors discuss the future perspectives for this promising class of agents. Expert opinion The knowledge gained thus far provides perhaps only a glimpse at the potential of HSP90 for which there is still much work to be done. Lessons from the clinical trials suggest that HSP90 therapy would advance at a faster pace if patient selection and tumor pharmacokinetics of these drugs were better understood and applied to their clinical development. It is also evident that combining HSP90 inhibitors with other potent anticancer therapies holds great promise not only due to synergistic antitumor activity but also due to the potential of prolonging or preventing the development of drug resistance.

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Discovery of XL888: A novel tropane-derived small molecule inhibitor of HSP90

Cited by 66 publications

References 32 publications

When Does Chemical Elaboration Induce a Ligand To Change Its Binding Mode?

When Does Chemical Elaboration Induce a Ligand To Change Its Binding Mode?

In Vivo Conformational Dynamics of Hsp90 and Its Interactors

Heat shock protein 90 inhibitors in the treatment of cancer: current status and future directions

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