Christine Chabot
Genentech
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Publication
Featured researches published by Christine Chabot.
Journal of Medicinal Chemistry | 2012
Brian Safina; Stewart Baker; Matt Baumgardner; Paul M. Blaney; Bryan K. Chan; Yung-Hsiang Chen; Matthew W. Cartwright; Georgette Castanedo; Christine Chabot; Arnaud J. Cheguillaume; Paul Goldsmith; David Michael Goldstein; Bindu Goyal; Timothy Colin Hancox; Raj K. Handa; Pravin S. Iyer; Jasmit Kaur; Rama K. Kondru; Jane R. Kenny; Sussie Lerche Krintel; Jun Li; John D. Lesnick; Matthew C. Lucas; Cristina Lewis; Sophie Mukadam; Jeremy Murray; Alan John Nadin; Jim Nonomiya; Fernando Padilla; Wylie Solang Palmer
PI3Kδ is a lipid kinase and a member of a larger family of enzymes, PI3K class IA(α, β, δ) and IB (γ), which catalyze the phosphorylation of PIP2 to PIP3. PI3Kδ is mainly expressed in leukocytes, where it plays a critical, nonredundant role in B cell receptor mediated signaling and provides an attractive opportunity to treat diseases where B cell activity is essential, e.g., rheumatoid arthritis. We report the discovery of novel, potent, and selective PI3Kδ inhibitors and describe a structural hypothesis for isoform (α, β, γ) selectivity gained from interactions in the affinity pocket. The critical component of our initial pharmacophore for isoform selectivity was strongly associated with CYP3A4 time-dependent inhibition (TDI). We describe a variety of strategies and methods for monitoring and attenuating TDI. Ultimately, a structure-based design approach was employed to identify a suitable structural replacement for further optimization.
Journal of Medicinal Chemistry | 2012
Jeremy Murray; Zachary Kevin Sweeney; Bryan K. Chan; Mercedesz Balazs; Erin K. Bradley; Georgette Castanedo; Christine Chabot; David Chantry; Michael Flagella; David Michael Goldstein; Rama K. Kondru; John D. Lesnick; Jun Li; Matthew C. Lucas; Jim Nonomiya; Jodie Pang; Stephen Price; Laurent Salphati; Brian Safina; Pascal Savy; Eileen Mary Seward; Mark Ultsch; Daniel P. Sutherlin
Inhibition of PI3Kδ is considered to be an attractive mechanism for the treatment of inflammatory diseases and leukocyte malignancies. Using a structure-based design approach, we have identified a series of potent and selective benzimidazole-based inhibitors of PI3Kδ. These inhibitors do not occupy the selectivity pocket between Trp760 and Met752 that is induced by other families of PI3Kδ inhibitors. Instead, the selectivity of the compounds for inhibition of PI3Kδ relative to other PI3K isoforms appears to be due primarily to the strong interactions these inhibitors are able to make with Trp760 in the PI3Kδ binding pocket. The pharmacokinetic properties and the ability of compound 5 to inhibit the function of B-cells in vivo are described.
Journal of Medicinal Chemistry | 2018
Thilo Focken; Sultan Chowdhury; Alla Yurevna Zenova; Michael Edward Grimwood; Christine Chabot; Tao Sheng; Ivan William Hemeon; Shannon Decker; Michael T. Wilson; Paul Robert Bichler; Qi Jia; Shaoyi Sun; Clint Young; Sophia Lin; Samuel J. Goodchild; Noah Gregory Shuart; Elaine Chang; Zhiwei Xie; Bowen Li; Kuldip Khakh; Girish Bankar; Matthew Waldbrook; Rainbow Kwan; Karen Nelkenbrecher; Parisa Karimi Tari; Navjot Chahal; Luis E. Sojo; C. Lee Robinette; Andrew D. White; Chien-An Chen
The sodium channel NaV1.7 has emerged as a promising target for the treatment of pain based on strong genetic validation of its role in nociception. In recent years, a number of aryl and acyl sulfonamides have been reported as potent inhibitors of NaV1.7, with high selectivity over the cardiac isoform NaV1.5. Herein, we report on the discovery of a novel series of N-([1,2,4]triazolo[4,3- a]pyridin-3-yl)methanesulfonamides as selective NaV1.7 inhibitors. Starting with the crystal structure of an acyl sulfonamide, we rationalized that cyclization to form a fused heterocycle would improve physicochemical properties, in particular lipophilicity. Our design strategy focused on optimization of potency for block of NaV1.7 and human metabolic stability. Lead compounds 10, 13 (GNE-131), and 25 showed excellent potency, good in vitro metabolic stability, and low in vivo clearance in mouse, rat, and dog. Compound 13 also displayed excellent efficacy in a transgenic mouse model of induced pain.
Journal of Medicinal Chemistry | 2012
James F. Blake; Rui Xu; Josef R. Bencsik; Dengming Xiao; Nicholas C. Kallan; Stephen T. Schlachter; Ian S. Mitchell; Keith L. Spencer; Anna L. Banka; Eli M. Wallace; Susan L. Gloor; Matthew Martinson; Richard Woessner; Guy Vigers; Barbara J. Brandhuber; Jun Liang; Brian Safina; Jun Li; Birong Zhang; Christine Chabot; Steven Do; Leslie Lee; Jason Oeh; Deepak Sampath; Brian Lee; Kui Lin; Bianca M. Liederer; Nicholas J. Skelton
Archive | 2014
Ian S. Mitchell; James F. Blake; Rui Xu; Nicholas C. Kallan; Dengming Xiao; Keith L. Spencer; Josef R. Bencsik; Eli M. Wallace; Stephen T. Schlachter; Anna L. Banka; Jun Liang; Brian Safina; Birong Zhang; Christine Chabot; Steven Do
Archive | 2007
Ian S. Mitchell; James F. Blake; Rui Xu; Nicholas C. Kallan; Dengming Xiao; Keith L. Spencer; Josef R. Bencsik; Jun Liang; Brian Safina; Birong Zhang; Christine Chabot; Steven Do; Eli W. Wallace; Anna L. Banka; Stephen T. Schlachter
Archive | 2009
Josef R. Bencsik; James F. Blake; Nicholas C. Kallan; Ian S. Mitchell; Keith L. Spencer; Dengming Xiao; Rui Xu; Christine Chabot; Steven Do; Jun Liang; Brian Safina; Birong Zhang; James M. Graham
Archive | 2009
Josef R. Bencsik; James F. Blake; Nicholas C. Kallan; Ian S. Mitchell; Keith L. Spencer; Dengming Xiao; Rui Xu; Christine Chabot; Steven Do; Jun Liang; Brian Safina; Birong Zhang
Archive | 2013
Ian S. Mitchell; エス. ミッチェル イアン; James F. Blake; エフ. ブレーク ジェームス; Rui Xu; ルイ スー; Nicholas C. Kallan; シー. カラン ニコラス; Dengming Xiao; デンミン シャオ; Keith L. Spencer; リー スペンサー キース; Josef R. Bencsik; アール. ベンシック ジョセフ; Jun Liang; チュン リャン; Brian Safina; サフィナ ブライアン; Chun Li; チュン リー; Christine Chabot; シャボー クリスティーヌ; Eli W. Wallace; エム. ウォレス エリー; Anna L. Banka; エル. バンカ アンナ; Stephen T. Schlachter; ティー. シュラヒター スティーブン
Archive | 2009
Josef R. Bencsik; James F. Blake; Nicholas C. Kallan; Ian S. Mitchell; Keith L. Spencer; Dengming Xiao; Rui Xu; Christine Chabot; Steven Do; Jun Liang; Brian Safina; Birong Zhang