Modular PROTAC Design for the Degradation of Oncogenic BCR-ABL.

Proteolysis Targeting Chimera (PROTAC) technology is a rapidly emerging alternative therapeutic strategy with the potential to address many of the challenges currently faced in modern drug development programs. PROTAC technology employs small molecules that recruit target proteins for ubiquitination and removal by the proteasome. The synthesis of PROTAC compounds that mediate the degradation of c-ABL and BCR-ABL by recruiting either Cereblon or Von Hippel Lindau E3 ligases is reported. During the course of their development, we discovered that the capacity of a PROTAC to induce degradation involves more than just target binding: the identity of the inhibitor warhead and the recruited E3 ligase largely determine the degradation profiles of the compounds; thus, as a starting point for PROTAC development, both the target ligand and the recruited E3 ligase should be varied to rapidly generate a PROTAC with the desired degradation profile.

[1]  I. E. Smith,et al.  Catalytic in vivo protein knockdown by small-molecule PROTACs. , 2015, Nature chemical biology.

[2]  James E. Bradner,et al.  Phthalimide conjugation as a strategy for in vivo target protein degradation , 2015, Science.

[3]  C. Crews,et al.  Hijacking the E3 Ubiquitin Ligase Cereblon to Efficiently Target BRD4. , 2015, Chemistry & biology.

[4]  A. Ciulli,et al.  Selective Small Molecule Induced Degradation of the BET Bromodomain Protein BRD4 , 2015, ACS chemical biology.

[5]  C. Ichim,et al.  Kinase‐Independent Mechanisms of Resistance of Leukemia Stem Cells to Tyrosine Kinase Inhibitors , 2014, Stem cells translational medicine.

[6]  Chad J. Miller,et al.  A comprehensive mathematical model for three-body binding equilibria. , 2013, Journal of the American Chemical Society.

[7]  Craig M. Crews,et al.  Niedermolekulare Inhibitoren der Wechselwirkung zwischen der E3-Ligase VHL und HIF1α† , 2012 .

[8]  W. L. Jorgensen,et al.  Small-molecule inhibitors of the interaction between the E3 ligase VHL and HIF1α. , 2012, Angewandte Chemie.

[9]  S. Boxer,et al.  Structural and Spectroscopic Analysis of the Kinase Inhibitor Bosutinib and an Isomer of Bosutinib Binding to the Abl Tyrosine Kinase Domain , 2012, PloS one.

[10]  G. Superti-Furga,et al.  BCR-ABL uncouples canonical JAK2-STAT5 signaling in chronic myeloid leukemia. , 2012, Nature chemical biology.

[11]  Julien Michel,et al.  Targeting the von Hippel–Lindau E3 Ubiquitin Ligase Using Small Molecules To Disrupt the VHL/HIF-1α Interaction , 2012, Journal of the American Chemical Society.

[12]  A. Hamilton,et al.  Chronic myeloid leukemia stem cells are not dependent on Bcr-Abl kinase activity for their survival. , 2012, Blood.

[13]  Yukihiro Itoh,et al.  Development of target protein-selective degradation inducer for protein knockdown. , 2011, Bioorganic & medicinal chemistry.

[14]  P. Ding,et al.  BCR-ABL tyrosine kinase inhibitors in the treatment of Philadelphia chromosome positive chronic myeloid leukemia: a review. , 2010, Leukemia research.

[15]  Jorge Cortes,et al.  Molecular biology of bcr-abl1-positive chronic myeloid leukemia. , 2009, Blood.

[16]  M. Wittekind,et al.  The structure of Dasatinib (BMS-354825) bound to activated ABL kinase domain elucidates its inhibitory activity against imatinib-resistant ABL mutants. , 2006, Cancer research.

[17]  G. Kroemer,et al.  A novel mechanism for imatinib mesylate-induced cell death of BCR-ABL-positive human leukemic cells: caspase-independent, necrosis-like programmed cell death mediated by serine protease activity. , 2004, Blood.

[18]  Oliver Hantschel,et al.  Regulation of the c-Abl and Bcr–Abl tyrosine kinases , 2004, Nature Reviews Molecular Cell Biology.

[19]  L. Allen.  Stem cells. , 2003, The New England journal of medicine.

[20]  David Boettiger,et al.  BCR-ABL-induced adhesion defects are tyrosine kinase-independent. , 2002, Blood.

[21]  John Kuriyan,et al.  Crystal structures of the kinase domain of c-Abl in complex with the small molecule inhibitors PD173955 and imatinib (STI-571). , 2001, Cancer research.

[22]  R. Deshaies,et al.  Protacs: Chimeric molecules that target proteins to the Skp1–Cullin–F box complex for ubiquitination and degradation , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[23]  Jürg Zimmermann,et al.  Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr–Abl positive cells , 1996, Nature Medicine.