Literature DB >> 27994749

Optimization of Highly Kinase Selective Bis-anilino Pyrimidine PAK1 Inhibitors.

William McCoull1, Edward J Hennessy2, Kevin Blades3, Claudio Chuaqui2, James E Dowling2, Andrew D Ferguson2, Frederick W Goldberg1, Nicholas Howe3, Christopher R Jones3, Paul D Kemmitt1, Gillian Lamont1, Jeffrey G Varnes2, Richard A Ward1, Bin Yang2.   

Abstract

Group I p21-activated kinase (PAK) inhibitors are indicated as important in cancer progression, but achieving high kinase selectivity has been challenging. A bis-anilino pyrimidine PAK1 inhibitor was identified and optimized through structure-based drug design to improve PAK1 potency and achieve high kinase selectivity, giving in vitro probe compound AZ13705339 (18). Reduction of lipophilicity to lower clearance afforded AZ13711265 (14) as an in vivo probe compound with oral exposure in mouse. Such probes will allow further investigation of PAK1 biology.

Entities:  

Keywords:  LLE; PAK; bis-anilino pyrimidine; kinase selectivity; probe

Year:  2016        PMID： 27994749      PMCID： PMC5150691          DOI： 10.1021/acsmedchemlett.6b00322

Source DB:  PubMed          Journal:  ACS Med Chem Lett        ISSN： 1948-5875            Impact factor:   4.345


  18 in total

1.  Impact of lipophilic efficiency on compound quality.

Authors:  Akos Tarcsay; Kinga Nyíri; György M Keseru
Journal:  J Med Chem       Date:  2012-01-24       Impact factor: 7.446

2.  Protein-ligand crystal structures can guide the design of selective inhibitors of the FGFR tyrosine kinase.

Authors:  Richard A Norman; Anne-Kathrin Schott; David M Andrews; Jason Breed; Kevin M Foote; Andrew P Garner; Derek Ogg; Jonathon P Orme; Jennifer H Pink; Karen Roberts; David A Rudge; Andrew P Thomas; Andrew G Leach
Journal:  J Med Chem       Date:  2012-05-21       Impact factor: 7.446

3.  Inhibitors of the tyrosine kinase EphB4. Part 4: Discovery and optimization of a benzylic alcohol series.

Authors:  Bernard Barlaam; Richard Ducray; Christine Lambert-van der Brempt; Patrick Plé; Catherine Bardelle; Nigel Brooks; Tanya Coleman; Darren Cross; Jason G Kettle; Jon Read
Journal:  Bioorg Med Chem Lett       Date:  2011-04-15       Impact factor: 2.823

4.  Small-molecule p21-activated kinase inhibitor PF-3758309 is a potent inhibitor of oncogenic signaling and tumor growth.

Authors:  Brion W Murray; Chuangxing Guo; Joseph Piraino; John K Westwick; Cathy Zhang; Jane Lamerdin; Eleanor Dagostino; Daniel Knighton; Cho-Ming Loi; Michael Zager; Eugenia Kraynov; Ian Popoff; James G Christensen; Ricardo Martinez; Susan E Kephart; Joseph Marakovits; Shannon Karlicek; Simon Bergqvist; Tod Smeal
Journal:  Proc Natl Acad Sci U S A       Date:  2010-05-03       Impact factor: 11.205

Review 5.  PAK signalling during the development and progression of cancer.

Authors:  Maria Radu; Galina Semenova; Rachelle Kosoff; Jonathan Chernoff
Journal:  Nat Rev Cancer       Date:  2014-01       Impact factor: 60.716

6.  p21-Activated Kinase 2 Regulates Endothelial Development and Function through the Bmk1/Erk5 Pathway.

Authors:  Maria Radu; Karen Lyle; Klaus P Hoeflich; Olga Villamar-Cruz; Hartmut Koeppen; Jonathan Chernoff
Journal:  Mol Cell Biol       Date:  2015-09-21       Impact factor: 4.272

7.  Inhibitors of p21-activated kinases (PAKs).

Authors:  Joachim Rudolph; James J Crawford; Klaus P Hoeflich; Weiru Wang
Journal:  J Med Chem       Date:  2014-12-03       Impact factor: 7.446

8.  Group I p21-activated kinases (PAKs) promote tumor cell proliferation and survival through the AKT1 and Raf-MAPK pathways.

Authors:  Craig W Menges; Eleonora Sementino; Jacqueline Talarchek; Jinfei Xu; Jonathan Chernoff; Jeffrey R Peterson; Joseph R Testa
Journal:  Mol Cancer Res       Date:  2012-07-12       Impact factor: 5.852

Review 9.  Role of p-21-activated kinases in cancer progression.

Authors:  Helen King; Nicole S Nicholas; Claire M Wells
Journal:  Int Rev Cell Mol Biol       Date:  2014       Impact factor: 6.813

10.  Effects of p21-activated kinase 1 inhibition on 11q13-amplified ovarian cancer cells.

Authors:  T Y Prudnikova; O Villamar-Cruz; S J Rawat; K Q Cai; J Chernoff
Journal:  Oncogene       Date:  2015-08-10       Impact factor: 9.867
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  8 in total

Review 1.  Targeting PAK1.

Authors:  Galina Semenova; Jonathan Chernoff
Journal:  Biochem Soc Trans       Date:  2017-02-08       Impact factor: 5.407

2.  PAK1 inhibitor IPA-3 mitigates metastatic prostate cancer-induced bone remodeling.

Authors:  Arti Verma; Sandeep Artham; Abdulrahman Alwhaibi; Mir S Adil; Brian S Cummings; Payaningal R Somanath
Journal:  Biochem Pharmacol       Date:  2020-03-30       Impact factor: 5.858

Review 3.  Regulating Cdc42 and Its Signaling Pathways in Cancer: Small Molecules and MicroRNA as New Treatment Candidates.

Authors:  Xing-Hua Xiao; Lin-Chen Lv; Jing Duan; Ye-Meng Wu; Shu-Jin He; Zhen-Zhen Hu; Li-Xia Xiong
Journal:  Molecules       Date:  2018-03-29       Impact factor: 4.411

4.  Solution structures and biophysical analysis of full-length group A PAKs reveal they are monomeric and auto-inhibited in cis.

Authors:  Fiona J Sorrell; Lena Marie Kilian; Jonathan M Elkins
Journal:  Biochem J       Date:  2019-04-04       Impact factor: 3.857

5.  Phosphorylation-dependent activity-based conformational changes in P21-activated kinase family members and screening of novel ATP competitive inhibitors.

Authors:  Mehreen Gul; Muhammad Fakhar; Sajid Rashid
Journal:  PLoS One       Date:  2019-11-18       Impact factor: 3.240

Review 6.  The role of cell division control protein 42 in tumor and non-tumor diseases: A systematic review.

Authors:  Junjie Fu; Bo Liu; Hao Zhang; Fangmei Fu; Xiaohui Yang; Linlin Fan; Minying Zheng; Shiwu Zhang
Journal:  J Cancer       Date:  2022-01-01       Impact factor: 4.207

7.  Sterically stabilized liposomes targeting P21 (RAC1) activated kinase-1 and secreted phospholipase A2 suppress prostate cancer growth and metastasis.

Authors:  Arti Verma; Wided Najahi-Missaoui; Brian S Cummings; Payaningal R Somanath
Journal:  Oncol Lett       Date:  2020-08-31       Impact factor: 2.967

8.  Siglec-8 Signals Through a Non-Canonical Pathway to Cause Human Eosinophil Death In Vitro.

Authors:  Daniela J Carroll; Yun Cao; Bruce S Bochner; Jeremy A O'Sullivan
Journal:  Front Immunol       Date:  2021-10-11       Impact factor: 7.561
  8 in total

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