Peter A. Petillo

ZIN Technologies (United States)

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Stephen F. Nelsen

University of Wisconsin–Madison

Scott Wise

LabCorp (United States)

Slawomir Z. Janicki

University of Illinois Urbana-Champaign

Pek Y. Chong

Research Triangle Park Foundation

Daniel L. Flynn

Deciphera Pharmaceuticals (United States)

Bryan K. S. Yeung

Novartis (Singapore)

Bryan D. Smith

Deciphera Pharmaceuticals (United States)

Daniel C. Hill

Brigham Young University

Brian J. Druker

Oregon Health & Science University

Christopher A. Eide

Oregon Health & Science University

Cooperative Institutions

University of Wisconsin–Madison

University of Kansas

University of Illinois Urbana-Champaign

Deciphera Pharmaceuticals (United States)

California Institute of Technology

University of Bristol

Oregon Health & Science University

Howard Hughes Medical Institute

Urbana University

University of Utah

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Small molecule modulators of B-Raf conformational switching pockets for treatment of human cancers. Inhibitors of wt and V600E, T529I/V600E mutant forms.

Molecular Cancer Therapeutics (2007)

Daniel L. Flynn M. J. Kaufman Wei Lü Peter A. Petillo Scott Wise

C212 Previously the only well-understood and general approach to kinase inhibition was based on small molecules which bind into the ATP cofactor pocket. While such an approach has been general, it has also been limited in success due to the overall conservation of the ATP pocket across the kinase family. Hence, selectivity and the ability to inhibit mutant and/or resistant forms of kinases have been met with only limited success. Deciphera Pharmaceuticals has developed a novel platform for kinase regulation which targets endogenous switch control pockets that exist in kinases. These pockets are used by kinases to regulate shape and catalytic activity in vivo . This presentation will highlight the attributes of targeting kinase switch control pockets in the development of B-Raf inhibitors for treatment of human cancers.  Deciphera’s B-Raf program has afforded potent inhibitors that achieve single digit nanomolar inhibition vs. wild-type and mutant forms of B-Raf including the T529I/V600E gatekeeper mutant and clinically significant V600E mutant. Our inhibitors retain this same level of potency in the presence of high ATP concentrations. In addition, cellular proliferation studies performed with various cells containing a V600E mutation have demonstrated excellent inhibitory profiles with achieved potencies in the low nanomolar range. We also have shown a defined mechanism of action by pMEK and pERK knockdown in these same cells. Recently compounds from our B-Raf program have demonstrated activity in an A375 mouse xenograft model with T-C values of at least 10 days and T/C values of 17%.  Deciphera’s B-Raf inhibitors also show acceptable ADME properties in cell permeability, cytochrome p450 inhibition, and microsomal clearance assays. Additional safety evaluations on key inhibitors have been successfully completed in hERG channel assays, Ames assays, and Cerep broad panel assessment. These data demonstrate that Deciphera’s technology has allowed for B-Raf inhibitors to be designed using mimicry of endogenous kinase regulation which has produced superior compounds that are poised for preclinical development.

V600E

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Comparison of free-energy changes for nitrogen inversion and electron loss. 3. 9-Halo-9-azabicyclo[3.3.1]nonanes

Journal of the American Chemical Society (1990)

Stephen F. Nelsen Peter A. Petillo Daniel T. Rumack

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTComparison of free-energy changes for nitrogen inversion and electron loss. 3. 9-Halo-9-azabicyclo[3.3.1]nonanesStephen F. Nelsen, Peter A. Petillo, and Daniel T. RumackCite this: J. Am. Chem. Soc. 1990, 112, 20, 7144–7147Publication Date (Print):September 1, 1990Publication History Published online1 May 2002Published inissue 1 September 1990https://pubs.acs.org/doi/10.1021/ja00176a010https://doi.org/10.1021/ja00176a010research-articleACS PublicationsRequest reuse permissionsArticle Views163Altmetric-Citations5LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose Get e-Alerts

Nitrogen inversion

10.1021/ja00176a010

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Citations (6)

β-1-N-Ureido-D-glucopyranose

Acta Crystallographica Section C Crystal Structure Communications (1998)

Jutta Blank Slawomir Z. Janicki Peter A. Petillo

β-1-N-Ureido-d-glucopyranose, C7H14N2O6, adopts a 4C1(D) conformation. The nearly planar urea moiety is in a Z-anti conformation.

D-Glucopyranose

10.1107/s0108270198007665

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Sequential Diels−Alder Reaction of in Situ Generated 2,3-Dimethylenepyrrole and Carbodienophiles: Rapid Synthesis of 2,3,6,7-Tetrasubstituted Carbazoles

Organic Letters (1999)

Jeffrey T. Vessels Slawomir Z. Janicki Peter A. Petillo

[reaction: see text] 2,3,6,7-Tetrasubstituted-1,2,3,4,5,6,7,8-octahydrocarbazoles 2 were synthesized in 46-90% yields by sequential Diels-Alder reactions from N-benzyl-2,5-dimethyl-3,4-bisacetoxymethylpyrrole (1) and dienophiles such as maleic anhydride, maleimides, ethyl maleate, fumaronitrile, and ethyl acrylate. The 2,3,6,7-tetrasubstituted carbazoles 3 were then synthesized in 32-87% yields from 2 by oxidation with DDQ.

Maleic anhydride

Ethyl acrylate

Diels–Alder reaction

10.1021/ol991220o

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Citations (25)

Origin and Quantitative Modeling of Anomeric Effect

ACS symposium series (1993)

Peter A. Petillo Laura Lerner

The origin of the anomeric effect has been examined by decomposing ab initio wavefunctions of dihydroxymethane (1) and dimethoxymethane (2) with the Natural Bond Orbital (NBO) method. The NBO analysis suggests that the anomeric effect arises from stabilizing 2-electron n(O)→σ*CO delocalizations. Geometry optimization of 1 and 2 in the absence of all n(O)→σ* interactions lengthens CO bond lengths by 0.06Å and reduces OCO bond angles. Optimization in the absence of all hyperconjugative interactions results in more dramatic changes in geometry (ΔrCO = 0.13Å, Δ

Natural bond orbital

Anomeric effect

Dimethoxymethane

Molecular geometry

Hyperconjugation

10.1021/bk-1993-0539.ch009

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Citations (34)

Patterned thin film enzyme electrodes via spincoating and glutaraldehyde vapor crosslinking: towards scalable fabrication of integrated sensor-on-CMOS devices

Lab on a Chip (2024)

Dvin Adalian Xiomi Madero Samson Chen Musab Jilani Richard D. Smith

Effective continuous glucose monitoring solutions require consistent sensor performance over the lifetime of the device, a manageable variance between devices, and the capability of high volume, low cost production. Here we present a novel and microfabrication-compatible method of depositing and stabilizing enzyme layers on top of planar electrodes that can aid in the mass production of sensors while also improving their consistency. This work is focused on the fragile biorecognition layer as that has been a critical difficulty in the development of microfabricated sensors. We test this approach with glucose oxidase (GOx) and evaluate the sensor performance with amperometric measurements of

Glutaraldehyde

10.1039/d4lc00206g

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Supplementary Tables 1-4, Figure 1 from The ABL Switch Control Inhibitor DCC-2036 Is Active against the Chronic Myeloid Leukemia Mutant BCR-ABL<sup>T315I</sup> and Exhibits a Narrow Resistance Profile

Christopher A. Eide Lauren T. Adrian Jeffrey W. Tyner Mary Mac Partlin David J Anderson

ABL

10.1158/0008-5472.22392068

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The nitrogen inversion barrier of 7-methyl-7-azabicyclo[2.2.1]heptane and the "bicyclic effect"

Journal of the American Chemical Society (1989)

Stephen F. Nelsen J. Thomas Ippoliti Timothy B. Frigo Peter A. Petillo

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTThe nitrogen inversion barrier of 7-methyl-7-azabicyclo[2.2.1]heptane and the "bicyclic effect"Stephen F. Nelsen, J. Thomas Ippoliti, Timothy B. Frigo, and Peter A. PetilloCite this: J. Am. Chem. Soc. 1989, 111, 5, 1776–1781Publication Date (Print):March 1, 1989Publication History Published online1 May 2002Published inissue 1 March 1989https://doi.org/10.1021/ja00187a034RIGHTS & PERMISSIONSArticle Views400Altmetric-Citations41LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (718 KB) Get e-AlertsSupporting Info (1)»Supporting Information Supporting Information Get e-Alerts

Heptane

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10.1021/ja00187a034

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Citations (44)

Applications and Methods for Continuous Monitoring of Physiological Chemistry

David A. Johnson Peter A. Petillo Daniel V. Aillon Mark L. Richter Philip Gao

Abstract : The overall goal of this project was to develop a platform methodology to clone, evolve, purify and stabilize high activity oxidase enzymes that are suitable for point-of-care diagnostic and human biosensor applications. The general approach was to add fusion proteins to increase enzyme stability without compromising enzyme activity. Oxidase enzymes that recognize lactate and histamine were improved, and an effort was made to develop a cortisol oxidase from cholesterol oxidase. These studies set the stage for a platform methodology to create biorecognition elements that are suitable for a wide range of point-of-care diagnostic devices.

10.21236/ada627115

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An active site mutation in 6-hydroxy-l-Nicotine oxidase from Arthrobacter nicotinovorans changes the substrate specificity in favor of (S)-nicotine

Archives of Biochemistry and Biophysics (2020)

Dwight O. Deay Kim K. Colvert Fei Gao Steve A. Seibold Priyanka Goyal

Arthrobacter

10.1016/j.abb.2020.108520

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Citations (4)