The High‐Resolution Solution Structure of Epothilone A Bound to Tubulin: An Understanding of the Structure–Activity Relationships for a Powerful Class of Antitumor Agents

Carlomagno, Teresa; Blommers, Marcel J. J.; Meiler, Jens; Jahnke, Wolfgang; Schupp, Thomas; Petersen, Frank; Schinzer, Dieter; Altmann, Karl‐Heinz; Griesinger, Christian

doi:10.1002/anie.200351276

Cited by 108 publications

(94 citation statements)

References 39 publications

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“…The potent activity of (14R)-methyl epothilone B in the range of IC 50 = 0.7-3.6 nM strongly supports the proposed bioactive conformation; the deoxy (14R)-methyl-epothilone D is less active against the cancer cell lines by a factor of about 25. These results are in accordance with the structure of 15N-labeled epothilone A obtained by high resolution NMR analysis in the presence of bovine tubulin [95]. An X-ray analysis of crystallized epothilone A revealed a very similar conformation to that of the studies mentioned before [96].…”

Section: Tubuline Stabilizing Agentssupporting

confidence: 79%

Aspects of Chirality in Natural Products Drug Discovery

Krastel

Petersen

Roggo

et al. 2006

Methods and Principles in Medicinal Chemistry

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Section: Tubuline Stabilizing Agentssupporting

confidence: 79%

Aspects of Chirality in Natural Products Drug Discovery

Krastel

Petersen

Roggo

et al. 2006

Methods and Principles in Medicinal Chemistry

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“…5C, left). The tubulin/BKM120 interaction was found to be in fast exchange as observed for other tubulin ligands (23). Furthermore, relaxation competition studies could not show binding to the colchicine site, when well-described tubulin colchicine site binders were used as competitors ( Supplementary Fig.…”

Section: Mol Cancer Ther; 11(8) August 2012mentioning

confidence: 74%

Characterization of the Mechanism of Action of the Pan Class I PI3K Inhibitor NVP-BKM120 across a Broad Range of Concentrations

Brachmann

Kleylein-Sohn

Gaulis

et al. 2012

Molecular Cancer Therapeutics

111

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The pan-phosphoinositide 3-kinase (PI3K) inhibitor BKM120 was found, at high concentrations, to cause cell death in various cellular systems, irrespective of their level of PI3K addiction. Transcriptional and biochemical profiling studies were used to identify the origin of these unexpected and apparently PI3K-independent effects. At 5-to 10-fold, the concentration needed to half-maximally inhibit PI3K signaling. BKM120 treatment caused changes in expression of mitotic genes and the induction of a robust G 2 -M arrest. Tubulin polymerization assays and nuclear magnetic resonance-binding studies revealed that BKM120 inhibited microtubule dynamics upon direct binding to tubulin. To assess the contribution of this off-target activity vis-a-vis the antitumor activity of BKM120 in PI3K-dependent tumors, we used a mechanistic PI3K-a-dependent model. We observed that, in vivo, daily treatment of mice with doses of BKM120 up to 40 mg/kg led to tumor regressions with no increase in the mitotic index. Thus, strong antitumor activity can be achieved in PI3K-dependent models at exposures that are below those necessary to engage the off-target activity. In comparison, the clinical data indicate that it is unlikely that BKM120 will achieve exposures sufficient to significantly engage the off-target activity at tolerated doses and schedules. However, in preclinical settings, the consequences of the off-target activity start to manifest themselves at concentrations above 1 mmol/L in vitro and doses above 50 mg/kg in efficacy studies using subcutaneous tumor-bearing mice. Hence, careful concentration and dose range selection is required to ensure that any observation can be correctly attributed to BKM120 inhibition of PI3K.

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“…The relationship between macrocycle conformation and the cytotoxicity of other epothilone analogs has been examined [14]. It has been found that when epothilones bind to tubulin, the C8-10 dihedral angle is approximately 1808 [15]. Thus, the unsaturation at C9-C10 may serve to lock the macrolide in a conformation for productive binding (Figure 4).…”

Section: Epothilonesmentioning

confidence: 97%

Novel biologically active natural and unnatural products

Myles¹

2003

Current Opinion in Biotechnology

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The High‐Resolution Solution Structure of Epothilone A Bound to Tubulin: An Understanding of the Structure–Activity Relationships for a Powerful Class of Antitumor Agents

Cited by 108 publications

References 39 publications

Aspects of Chirality in Natural Products Drug Discovery

Aspects of Chirality in Natural Products Drug Discovery

Characterization of the Mechanism of Action of the Pan Class I PI3K Inhibitor NVP-BKM120 across a Broad Range of Concentrations

Novel biologically active natural and unnatural products

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