Design and Optimization of Potent and Orally Bioavailable Tetrahydronaphthalene Raf Inhibitors

Gould, Alexandra E.; Adams, Ruth; Adhikari, Subash; Aertgeerts, K.; Afroze, Roushan; Blackburn, Christopher; Calderwood, Emily F.; Chau, Ryan; Chouitar, Johara; Duffey, Matthew O.; England, Dylan B.; Farrer, Cheryl A; Forsyth, Nancy; Garcia, Khristofer; Gaulin, Jeffery; Greenspan, Paul D.; Guo, Ribo; Harrison, Sean; Huang, Shih-Chung; Iartchouk, Natalia; Janowick, Dave; Kim, Misook; Kulkarni, B. A.; Langston, Steven; Liu, Jane X.; Ma, Li‐Ting; Menon, Saurabh; Mizutani, Hirotake; Paske, Erin; Renou, Christelle C.; Rezaei, Mansoureh; Rowland, R. Scott; Sintchak, Michael D.; Smith, Michael D.; Stroud, Stephen G.; Tregay, Ming; Tian, Yuan; Veiby, O. Petter; Vos, Tricia J.; Vyskočil, Štěpán; Williams, Juliet; Xu, Tianlin; Yang, Johnny; Yano, Jason; Zeng, Hongbo; Zhang, Dong Mei; Zhang, Qin; Galvin, Katherine

doi:10.1021/jm101479y

Cited by 33 publications

(14 citation statements)

References 23 publications

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“…LGX818 inhibited monomer driven signaling at 14 nM, and dimer signaling at 287 nM, despite its high potency and low off-rate (see below.). By contrast, BGB659, a type II, ATP-competitive RAF inhibitor (compound 27 from Gould et al, 2011) inhibited ERK signaling driven by p61 BRAF V600E dimers and BRAF V600E monomers at similar doses (Figure 4B and Figure. S4D).…”

Section: Resultsmentioning

confidence: 96%

BRAF Mutants Evade ERK-Dependent Feedback by Different Mechanisms that Determine Their Sensitivity to Pharmacologic Inhibition

et al. 2015

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Summary ERK signaling requires RAS-induced RAF dimerization and is limited by feedback. Activated BRAF mutants evade feedback inhibition of RAS by either of two mechanisms. BRAF V600 mutants are activated monomers when RAS activity is low; all other activating BRAF mutants function as constitutive RAS-independent dimers. RAF inhibitors effectively inhibit mutant monomers, but not dimers; their binding to one site in the dimer significantly reduces their affinity for the second. Tumors with non-V600E BRAF mutants are insensitive to these drugs and increased expression of BRAF V600E dimers causes acquired resistance. A compound that equally inhibits both sites of mutant RAF dimers inhibits tumors driven by either class of mutants or those BRAF V600E tumors with dimer-dependent acquired resistance to monomer-specific inhibitors.

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Section: Resultsmentioning

confidence: 96%

BRAF Mutants Evade ERK-Dependent Feedback by Different Mechanisms that Determine Their Sensitivity to Pharmacologic Inhibition

et al. 2015

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“…We suggest that this may be a broader mechanism of Type II kinase inhibitors (that target non-phosphorylated/inactivated kinases). In addition to TYK2, we find that the 1159-1071 equivalent Arg-Glu pair is the global connectivity hub for the serine-threonine oncoprotein kinase BRAF 31 in the non-phosphorylated form ( Figure 4D ). More generically, we suggest that ultra-conserved structural elements (such as the R1159-E1071 pair of TYK2) within each oncoprotein family may be prime candidates for experimental and clinical studies to determine disease causality.…”

Section: Resultsmentioning

confidence: 99%

Global connectivity of hub residues in Oncoprotein structures encodes genetic factors dictating personalized drug response to targeted Cancer therapy

Soundararajan¹,

Aravamudan²

2014

Sci Rep

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The efficacy and mechanisms of therapeutic action are largely described by atomic bonds and interactions local to drug binding sites. Here we introduce global connectivity analysis as a high-throughput computational assay of therapeutic action – inspired by the Google page rank algorithm that unearths most “globally connected” websites from the information-dense world wide web (WWW). We execute short timescale (30 ps) molecular dynamics simulations with high sampling frequency (0.01 ps), to identify amino acid residue hubs whose global connectivity dynamics are characteristic of the ligand or mutation associated with the target protein. We find that unexpected allosteric hubs – up to 20Å from the ATP binding site, but within 5Å of the phosphorylation site – encode the Gibbs free energy of inhibition (ΔGinhibition) for select protein kinase-targeted cancer therapeutics. We further find that clinically relevant somatic cancer mutations implicated in both drug resistance and personalized drug sensitivity can be predicted in a high-throughput fashion. Our results establish global connectivity analysis as a potent assay of protein functional modulation. This sets the stage for unearthing disease-causal exome mutations and motivates forecast of clinical drug response on a patient-by-patient basis. We suggest incorporation of structure-guided genetic inference assays into pharmaceutical and healthcare Oncology workflows.

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“…29 We postulated that this interaction is also present for fragment 1R (Figure 3c). This hypothesis was further corroborated with the synthesis of compounds 8R and 9R.…”

Section: Acs Medicinal Chemistry Lettersmentioning

confidence: 84%

Diversity-Oriented Synthesis as a Strategy for Fragment Evolution against GSK3β

Wang

Wach

Sheehan

et al. 2016

ACS Med. Chem. Lett.

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Traditional fragment-based drug discovery (FBDD) relies heavily on structural analysis of the hits bound to their targets. Herein, we present a complementary approach based on diversity-oriented synthesis (DOS). A DOS-based fragment collection was able to produce initial hit compounds against the target GSK3β, allow the systematic synthesis of related fragment analogues to explore fragment-level structure−activity relationship, and finally lead to the synthesis of a more potent compound.

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Design and Optimization of Potent and Orally Bioavailable Tetrahydronaphthalene Raf Inhibitors

Cited by 33 publications

References 23 publications

BRAF Mutants Evade ERK-Dependent Feedback by Different Mechanisms that Determine Their Sensitivity to Pharmacologic Inhibition

BRAF Mutants Evade ERK-Dependent Feedback by Different Mechanisms that Determine Their Sensitivity to Pharmacologic Inhibition

Global connectivity of hub residues in Oncoprotein structures encodes genetic factors dictating personalized drug response to targeted Cancer therapy

Diversity-Oriented Synthesis as a Strategy for Fragment Evolution against GSK3β

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