Discovery of Selective and Noncovalent Diaminopyrimidine-Based Inhibitors of Epidermal Growth Factor Receptor Containing the T790M Resistance Mutation

Hanan, Emily J.; Eigenbrot, Charles; Bryan, Marian C.; Burdick, Daniel J.; Chan, Bryan; Chen, Yuan; Dotson, Jennafer; Heald, Robert A.; Jackson, Patrick N. Wyse; La, Hank; Lainchbury, Michael; Malek, Shiva; Purkey, Hans E.; Schaefer, Gabriele; Schmidt, Stephen; Seward, Eileen M.; Sideris, Steve; Tam, Christine; Wang, Shumei; Yeap, Siew Kuen; Yen, Ivana; Yin, Jianping; Yu, Christine; Zilberleyb, Inna; Heffron, Timothy P.

doi:10.1021/jm501578n

Cited by 55 publications

(57 citation statements)

References 43 publications

(91 reference statements)

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“…Potency in the biochemical assay against the TMdel enzyme is significantly weaker than TMLR, a trend which was not evident in earlier analogues. 39 However, cell potency, which is obviously more important, is actually better against PC9(ER) than H1975. Increased proliferation potency in the PC9(ER) cells could be due to greater sensitivity to inhibition of the EGFR pathway, but this should not affect pEGFR EC 50 .…”

Section: Resultsmentioning

confidence: 99%

“…Crystallographic methods and the production and use of TMLR proteins were as previously described 39 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 55 al. 73 Purified wild-type EGFR kinase domain was crystallized in 1:1 ratio (2.5µl protein: 2.5µl well solution) containing 1M Na/K tartrate, 0.1M Mes pH7.…”

Section: H-imidazo[45 -C]pyridin-6-ylamino]pyrimidin-2-yl}piperidinmentioning

confidence: 99%

“…MoKa software (version 1.1.0, Molecular Discovery) was used to calculate the logarithm of the partition coefficient (cLogP).Kinetic solubility. Solubility determination was as previously described 39. …”

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confidence: 99%

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Noncovalent Mutant Selective Epidermal Growth Factor Receptor Inhibitors: A Lead Optimization Case Study

Heald

Bowman²,

Bryan³

et al. 2015

J. Med. Chem.

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Because of their increased activity against activating mutants, first-generation epidermal growth factor receptor (EGFR) kinase inhibitors have had remarkable success in treating non-small-cell lung cancer (NSCLC) patients, but acquired resistance, through a secondary mutation of the gatekeeper residue, means that clinical responses only last for 8-14 months. Addressing this unmet medical need requires agents that can target both of the most common double mutants: T790M/L858R (TMLR) and T790M/del(746-750) (TMdel). Herein we describe how a noncovalent double mutant selective lead compound was optimized using a strategy focused on the structure-guided increase in potency without added lipophilicity or reduction of three-dimensional character. Following successive rounds of design and synthesis it was discovered that cis-fluoro substitution on 4-hydroxy- and 4-methoxypiperidinyl groups provided synergistic, substantial, and specific potency gain through direct interaction with the enzyme and/or effects on the proximal ligand oxygen atom. Further development of the fluorohydroxypiperidine series resulted in the identification of a pair of diastereomers that showed 50-fold enzyme and cell based selectivity for T790M mutants over wild-type EGFR (wtEGFR) in vitro and pathway knock-down in an in vivo xenograft model.

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Section: Resultsmentioning

confidence: 99%

Section: H-imidazo[45 -C]pyridin-6-ylamino]pyrimidin-2-yl}piperidinmentioning

confidence: 99%

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Noncovalent Mutant Selective Epidermal Growth Factor Receptor Inhibitors: A Lead Optimization Case Study

Heald

Bowman²,

Bryan³

et al. 2015

J. Med. Chem.

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“…An effort to design inhibitors of the nitric oxide synthase oxygenase, serving as antibiotics against Gram-positive pathogens, utilized a variant of the enzyme predicted by SERp [156–159]: 46 respective PDB entries are available. Finally, the epidermal growth factor receptor kinase domain, a target for non-small cell lung cancer, has been successfully engineered to yield 21 PDB depositions of complexes with drug leads [160–162]. …”

Section: Target Protein Modification For Enhanced Crystallizabilitymentioning

confidence: 99%

The “Sticky Patch” Model of Crystallization and Modification of Proteins for Enhanced Crystallizability

Derewenda

Godzik

2017

Methods in Molecular Biology

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Crystallization of macromolecules has long been perceived as a stochastic process, which cannot be predicted or controlled. This is consistent with another popular notion that the interactions of molecules within the crystal, i.e. crystal contacts, are essentially random and devoid of specific physicochemical features. In contrast, functionally relevant surfaces, such as oligomerization interfaces and specific protein-protein interaction sites, are under evolutionary pressures so their amino acid composition, structure and topology are distinct. However, current theoretical and experimental studies are significantly changing our understanding of the nature of crystallization. The increasingly popular ‘sticky patch’ model, derived from soft matter physics, describes crystallization as a process driven by interactions between select, specific surface patches, with properties thermodynamically favorable for cohesive interactions. Independent support for this model comes from various sources including structural studies and bioinformatics. Proteins that are recalcitrant to crystallization can be modified for enhanced crystallizability through chemical or mutational modification of their surface to effectively engineer ‘sticky patches’ which would drive crystallization. Here, we discuss the current state of knowledge of the relationship between the microscopic properties of the target macromolecule and its crystallizability, focusing on the ‘sticky patch’ model. We discuss state-of-art in silico methods that evaluate the propensity of a given target protein to form crystals based on these relationships, with the objective to design of variants with modified molecular surface properties and enhanced crystallization propensity. We illustrate this discussion with specific cases where these approaches allowed to generate crystals suitable for structural analysis.

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“…Recent disclosures by Clovis Oncology and Astra-Zeneca revealed their clinical candidates CO-1686 16 and AZD-9291 [17][18][19] which possess selectivity for the EGFR L858R,T790M mutant over EGFR WT . [20][21][22] Our efforts in this area began with compound 1 which was the result of structure-guided design. Inspired by our previous research efforts on p38 MAP kinase 23,24 and the structural similarities of the ATP binding pockets of p38 and EGFR we explored the fusion of a pyridone ring onto the scaffold of WZ-4002 ( Figure 3).…”

mentioning

confidence: 99%

Oxopyrido[2,3-d]pyrimidines as Covalent L858R/T790M Mutant Selective Epidermal Growth Factor Receptor (EGFR) Inhibitors

Wurz

Pettus

Ashton

et al. 2015

ACS Med. Chem. Lett.

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In nonsmall cell lung cancer (NSCLC), the threonine(790)-methionine(790) (T790M) point mutation of EGFR kinase is one of the leading causes of acquired resistance to the first generation tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib. Herein, we describe the optimization of a series of 7-oxopyrido[2,3-d]pyrimidinyl-derived irreversible inhibitors of EGFR kinase. This led to the discovery of compound 24 which potently inhibits gefitinib-resistant EGFR(L858R,T790M) with 100-fold selectivity over wild-type EGFR. Compound 24 displays strong antiproliferative activity against the H1975 nonsmall cell lung cancer cell line, the first line mutant HCC827 cell line, and promising antitumor activity in an EGFR(L858R,T790M) driven H1975 xenograft model sparing the side effects associated with the inhibition of wild-type EGFR.

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Discovery of Selective and Noncovalent Diaminopyrimidine-Based Inhibitors of Epidermal Growth Factor Receptor Containing the T790M Resistance Mutation

Cited by 55 publications

References 43 publications

Noncovalent Mutant Selective Epidermal Growth Factor Receptor Inhibitors: A Lead Optimization Case Study

Noncovalent Mutant Selective Epidermal Growth Factor Receptor Inhibitors: A Lead Optimization Case Study

The “Sticky Patch” Model of Crystallization and Modification of Proteins for Enhanced Crystallizability

Oxopyrido[2,3-d]pyrimidines as Covalent L858R/T790M Mutant Selective Epidermal Growth Factor Receptor (EGFR) Inhibitors

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