Design and Synthesis of Functionally Active 5-Amino-6-Aryl Pyrrolopyrimidine Inhibitors of Hematopoietic Progenitor Kinase 1.

Immune activating agents represent a valuable class of therapeutics for the treatment of cancer. An area of active research is expanding the types of these therapeutics that are available to patients via targeting new biological mechanisms. Hematopoietic progenitor kinase 1 (HPK1) is a negative regulator of immune signaling and a target of high interest for the treatment of cancer. Herein, we present the discovery and optimization of novel amino-6-aryl pyrrolopyrimidine inhibitors of HPK1 starting from hits identified via virtual screening. Key components of this discovery effort were structure-based drug design aided by analyses of normalized B-factors and optimization of lipophilic efficiency.

[1]  Q. You,et al.  Hematopoietic Progenitor Kinase 1 in Tumor Immunology: A Medicinal Chemistry Perspective. , 2022, Journal of medicinal chemistry.

[2]  M. McTigue,et al.  Multiple conformational states of the HPK1 kinase domain in complex with sunitinib reveal the structural changes accompanying HPK1 trans-regulation , 2019, The Journal of Biological Chemistry.

[3]  J. Hunt,et al.  Critical role of kinase activity of hematopoietic progenitor kinase 1 in anti-tumor immune surveillance , 2019, PloS one.

[4]  I. Mellman,et al.  The Kinase Activity of Hematopoietic Progenitor Kinase 1 Is Essential for the Regulation of T Cell Function. , 2018, Cell reports.

[5]  D. Gehlhaar,et al.  Reviving B-Factors: Activating ALK Mutations Increase Protein Dynamics of the Unphosphorylated Kinase. , 2018, ACS medicinal chemistry letters.

[6]  D. Gehlhaar,et al.  Reviving B-Factors: Retrospective Normalized B-Factor Analysis of c-ros Oncogene 1 Receptor Tyrosine Kinase and Anaplastic Lymphoma Kinase L1196M with Crizotinib and Lorlatinib. , 2018, ACS medicinal chemistry letters.

[7]  M. Edwards,et al.  Lipophilic Efficiency as an Important Metric in Drug Design. , 2018, Journal of medicinal chemistry.

[8]  A. Alcover,et al.  Serine Phosphorylation of SLP76 Is Dispensable for T Cell Development but Modulates Helper T Cell Function , 2017, PloS one.

[9]  N. Sach,et al.  Diastereoselective access to substituted 4-aminopiperidines via a pyridine reduction approach , 2016 .

[10]  R. Kurumbail,et al.  Discovery and preclinical profiling of 3-[4-(morpholin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]benzonitrile (PF-06447475), a highly potent, selective, brain penetrant, and in vivo active LRRK2 kinase inhibitor. , 2015, Journal of medicinal chemistry.

[11]  S. Sawasdikosol,et al.  HPK1 as a novel target for cancer immunotherapy , 2012, Immunologic research.

[12]  Mindy I. Davis,et al.  Comprehensive analysis of kinase inhibitor selectivity , 2011, Nature Biotechnology.

[13]  Li Di,et al.  Development of a new permeability assay using low-efflux MDCKII cells. , 2011, Journal of pharmaceutical sciences.

[14]  Clemens Vonrhein,et al.  Data processing and analysis with the autoPROC toolbox , 2011, Acta crystallographica. Section D, Biological crystallography.

[15]  S. Rabindran,et al.  Structure-based design of potent and selective 3-phosphoinositide-dependent kinase-1 (PDK1) inhibitors. , 2011, Journal of medicinal chemistry.

[16]  Anna Vulpetti,et al.  Tautomer Preference in PDB Complexes and its Impact on Structure-Based Drug Discovery , 2010, J. Chem. Inf. Model..

[17]  H. Yee,et al.  Hematopoietic progenitor kinase 1 is a critical component of prostaglandin E2-mediated suppression of the anti-tumor immune response , 2009, Cancer Immunology, Immunotherapy.

[18]  S. Alzabin,et al.  Hematopoietic Progenitor Kinase 1 Is a Negative Regulator of Dendritic Cell Activation , 2009, The Journal of Immunology.

[19]  Loriano Storchi,et al.  Tautomer Enumeration and Stability Prediction for Virtual Screening on Large Chemical Databases , 2009, J. Chem. Inf. Model..

[20]  Loriano Storchi,et al.  New and Original pKa Prediction Method Using Grid Molecular Interaction Fields , 2007, J. Chem. Inf. Model..

[21]  W. Lehmann,et al.  A novel pathway down-modulating T cell activation involves HPK-1–dependent recruitment of 14-3-3 proteins on SLP-76 , 2007, The Journal of experimental medicine.

[22]  Kevin Cowtan,et al.  research papers Acta Crystallographica Section D Biological , 2005 .

[23]  Rita Greco,et al.  Catalytic Domain Crystal Structure of Protein Kinase C-θ (PKCθ)*♦ , 2004, Journal of Biological Chemistry.

[24]  Arthur Weiss,et al.  Hematopoietic Progenitor Kinase 1 Associates Physically and Functionally with the Adaptor Proteins B Cell Linker Protein and SLP-76 in Lymphocytes* , 2001, The Journal of Biological Chemistry.

[25]  R. Rourick,et al.  High throughput log D determination using liquid chromatography-mass spectrometry. , 2001, Combinatorial chemistry & high throughput screening.

[26]  A. Altman,et al.  Protein kinase Cθ: a new essential superstar on the T-cell stage , 2000 .

[27]  M. Cobb,et al.  HPK1 is activated by lymphocyte antigen receptors and negatively regulates AP-1. , 2000, Immunity.

[28]  Abraham Nudelman,et al.  NMR Chemical Shifts of Common Laboratory Solvents as Trace Impurities. , 1997, The Journal of organic chemistry.

[29]  J F Morrison,et al.  Kinetics of the reversible inhibition of enzyme-catalysed reactions by tight-binding inhibitors. , 1969, Biochimica et biophysica acta.

[30]  T. Tan,et al.  Hematopoietic progenitor kinase 1 negatively regulates T cell receptor signaling and T cell–mediated immune responses , 2007, Nature Immunology.