Development of isoform selective PI3-kinase inhibitors as pharmacological tools for elucidating the PI3K pathway

Bruce, Ian; Akhlaq, Mohammed Shahid; Bloomfield, Graham C.; Budd, Emma; Cox, Brian J.; Cuenoud, Bernard; Finan, Peter M.; Gedeck, Peter; Hatto, Julia; Hayler, Judy; Head, Denise; Keller, Thomas H.; Kirman, Louise; Leblanc, Catherine; Grand, Darren Le; McCarthy, Clive; O’Connor, Desmond; Owen, Catherine; Oza, Mrinalini S.; Pilgrim, Gaynor; Press, Nicola E.; Sviridenko, Lilya; Whitehead, Lewis

doi:10.1016/j.bmcl.2012.07.042

Cited by 46 publications

(27 citation statements)

References 21 publications

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“…The 2-aminothiazole scaffold was selected as a starting point for the development of potent and selective PI3K inhibitors based on its binding mode, indicating the potential to use substituents at the amino group to develop interactions with nonconserved amino acids at the ATP pocket entrance (21). Consequently, systematic modification of key moieties and optimization of the drug-like properties led to the identification of NVP-BYL719 (18).…”

Section: Nvp-byl719 Potently and Selectively Inhibits Pi3ka In Vitromentioning

confidence: 99%

Characterization of the Novel and Specific PI3Kα Inhibitor NVP-BYL719 and Development of the Patient Stratification Strategy for Clinical Trials

Fritsch

Huang

Chatenay‐Rivauday

et al. 2014

Molecular Cancer Therapeutics

381

328

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Somatic PIK3CA mutations are frequently found in solid tumors, raising the hypothesis that selective inhibition of PI3Ka may have robust efficacy in PIK3CA-mutant cancers while sparing patients the side-effects associated with broader inhibition of the class I phosphoinositide 3-kinase (PI3K) family. Here, we report the biologic properties of the 2-aminothiazole derivative NVP-BYL719, a selective inhibitor of PI3Ka and its most common oncogenic mutant forms. The compound selectivity combined with excellent drug-like properties translates to dose-and time-dependent inhibition of PI3Ka signaling in vivo, resulting in robust therapeutic efficacy and tolerability in PIK3CA-dependent tumors. Novel targeted therapeutics such as NVP-BYL719, designed to modulate aberrant functions elicited by cancer-specific genetic alterations upon which the disease depends, require well-defined patient stratification strategies in order to maximize their therapeutic impact and benefit for the patients. Here, we also describe the application of the Cancer Cell Line Encyclopedia as a preclinical platform to refine the patient stratification strategy for NVP-BYL719 and found that PIK3CA mutation was the foremost positive predictor of sensitivity while revealing additional positive and negative associations such as PIK3CA amplification and PTEN mutation, respectively. These patient selection determinants are being assayed in the ongoing NVP-BYL719 clinical trials.

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Section: Nvp-byl719 Potently and Selectively Inhibits Pi3ka In Vitromentioning

confidence: 99%

Characterization of the Novel and Specific PI3Kα Inhibitor NVP-BYL719 and Development of the Patient Stratification Strategy for Clinical Trials

Fritsch

Huang

Chatenay‐Rivauday

et al. 2014

Molecular Cancer Therapeutics

381

328

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“…23,24 The urea functional group was chosen, since it allowed rapid structure−activity profiling via straightforward coupling reactions with amines (see Supporting Information). Increasing the urea chain length resulted in compounds with improved PI3Kγ affinity ( Table 2, 17, 18 vs 14−16).…”

mentioning

confidence: 99%

Structural Basis for Isoform Selectivity in a Class of Benzothiazole Inhibitors of Phosphoinositide 3-Kinase γ

et al. 2014

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Phosphoinositide 3-kinase γ (PI3Kγ) is an attractive target to potentially treat a range of disease states. Herein, we describe the evolution of a reported phenylthiazole pan-PI3K inhibitor into a family of potent and selective benzothiazole inhibitors. Using X-ray crystallography, we discovered that compound 22 occupies a previously unreported hydrophobic binding cleft adjacent to the ATP binding site of PI3Kγ, and achieves its selectivity by exploiting natural sequence differences among PI3K isoforms in this region.

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“…3,5 Applying the same annulation leads to the 4,5-dihydrothiazolo [4,5-h]quinazoline analogues of the general structure 14, as depicted in Figure 4.…”

Section: Introductionmentioning

confidence: 97%

“…4 This formed part of a broader piece of work which started from the hit structures, exemplified by 1 in Figure 2, and culminated in the identification of alpelisib. 5,6 In this Letter we describe an additional extension of this work in which a further annulation was introduced to generate the tricyclic 4,5-dihydrobenzo [1,2-d:3,4-d]bisthiazole core, as exemplified by the general structure 2.…”

Section: Introductionmentioning

confidence: 98%

Identification and optimisation of 4,5-dihydrobenzo[1,2-d:3,4-d]bisthiazole and 4,5-dihydrothiazolo[4,5-h]quinazoline series of selective phosphatidylinositol-3 kinase alpha inhibitors

Fairhurst

Gerspacher

Imbach‐Weese

et al. 2015

Bioorganic & Medicinal Chemistry Letters

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Development of isoform selective PI3-kinase inhibitors as pharmacological tools for elucidating the PI3K pathway

Cited by 46 publications

References 21 publications

Characterization of the Novel and Specific PI3Kα Inhibitor NVP-BYL719 and Development of the Patient Stratification Strategy for Clinical Trials

Characterization of the Novel and Specific PI3Kα Inhibitor NVP-BYL719 and Development of the Patient Stratification Strategy for Clinical Trials

Structural Basis for Isoform Selectivity in a Class of Benzothiazole Inhibitors of Phosphoinositide 3-Kinase γ

Identification and optimisation of 4,5-dihydrobenzo[1,2-d:3,4-d]bisthiazole and 4,5-dihydrothiazolo[4,5-h]quinazoline series of selective phosphatidylinositol-3 kinase alpha inhibitors

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