title: Battling Btk Mutants With Noncovalent Inhibitors That Overcome Cys481 and Thr474 Mutations.
abstract: The Bruton's tyrosine kinase (Btk) inhibitor ibrutinib has shown impressive clinical efficacy in a range of B-cell malignancies. However, acquired resistance has emerged, and second generation therapies are now being sought. Ibrutinib is a covalent, irreversible inhibitor that modifies Cys481 in the ATP binding site of Btk and renders the enzyme inactive, thereby blocking B-cell receptor signal transduction. Not surprisingly, Cys481 is the most commonly mutated Btk residue in cases of acquired resistance to ibrutinib. Mutations at other sites, including Thr474, a gatekeeper residue, have also been detected. Herein, we describe noncovalent Btk inhibitors that differ from covalent inhibitors like ibrutinib in that they do not interact with Cys481, they potently inhibit the ibrutinib-resistant Btk C481S mutant in vitro and in cells, and they are exquisitely selective for Btk. Noncovalent inhibitors such as GNE-431 also show excellent potency against the C481R, T474I, and T474M mutants. X-ray crystallographic analysis of Btk provides insight into the unique mode of binding of these inhibitors that explains their high selectivity for Btk and their retained activity against mutant forms of Btk. This class of noncovalent Btk inhibitors may provide a treatment option to patients, especially those who have acquired resistance to ibrutinib by mutation of Cys481 or Thr474.
authors: Biochemical and Cellular Pharmacology, Genentech , 1 DNA Way, South San Francisco, California 94080, United States.
authors: Adam R
authors: AR
authors: Johnson
authors: Biochemical and Cellular Pharmacology, Genentech , 1 DNA Way, South San Francisco, California 94080, United States.
authors: Pawan Bir
authors: PB
authors: Kohli
authors: Discovery Immunology, Genentech , 1 DNA Way, South San Francisco, California 94080, United States.
authors: Arna
authors: A
authors: Katewa
authors: Discovery Immunology, Genentech , 1 DNA Way, South San Francisco, California 94080, United States.
authors: Emily
authors: E
authors: Gogol
authors: Discovery Oncology, Genentech , 1 DNA Way, South San Francisco, California 94080, United States.
authors: Lisa D
authors: LD
authors: Belmont
authors: Discovery Oncology, Genentech , 1 DNA Way, South San Francisco, California 94080, United States.
authors: Regina
authors: R
authors: Choy
authors: Biomarker Development, Genentech , 1 DNA Way, South San Francisco, California 94080, United States.
authors: Elicia
authors: E
authors: Penuel
authors: Biomarker Development, Genentech , 1 DNA Way, South San Francisco, California 94080, United States.
authors: Luciana
authors: L
authors: Burton
authors: Protein Chemistry and Structural Biology, Genentech , 1 DNA Way, South San Francisco, California 94080, United States.
authors: Charles
authors: C
authors: Eigenbrot
authors: Protein Chemistry and Structural Biology, Genentech , 1 DNA Way, South San Francisco, California 94080, United States.
authors: Christine
authors: C
authors: Yu
authors: Computational Chemistry, Genentech , 1 DNA Way, South San Francisco, California 94080, United States.
authors: Daniel F
authors: DF
authors: Ortwine
authors: Protein Chemistry and Structural Biology, Genentech , 1 DNA Way, South San Francisco, California 94080, United States.
authors: Krista
authors: K
authors: Bowman
authors: Protein Chemistry and Structural Biology, Genentech , 1 DNA Way, South San Francisco, California 94080, United States.
authors: Yvonne
authors: Y
authors: Franke
authors: Protein Chemistry and Structural Biology, Genentech , 1 DNA Way, South San Francisco, California 94080, United States.
authors: Christine
authors: C
authors: Tam
authors: Protein Chemistry and Structural Biology, Genentech , 1 DNA Way, South San Francisco, California 94080, United States.
authors: Alberto
authors: A
authors: Estevez
authors: Protein Chemistry and Structural Biology, Genentech , 1 DNA Way, South San Francisco, California 94080, United States.
authors: Kyle
authors: K
authors: Mortara
authors: Protein Chemistry and Structural Biology, Genentech , 1 DNA Way, South San Francisco, California 94080, United States.
authors: Jiansheng
authors: J
authors: Wu
authors: Protein Chemistry and Structural Biology, Genentech , 1 DNA Way, South San Francisco, California 94080, United States.
authors: Hong
authors: H
authors: Li
authors: Protein Chemistry and Structural Biology, Genentech , 1 DNA Way, South San Francisco, California 94080, United States.
authors: May
authors: M
authors: Lin
authors: Discovery Chemistry, Genentech , 1 DNA Way, South San Francisco, California 94080, United States.
authors: Philippe
authors: P
authors: Bergeron
authors: Discovery Chemistry, Genentech , 1 DNA Way, South San Francisco, California 94080, United States.
authors: James J
authors: JJ
authors: Crawford
authors: Discovery Chemistry, Genentech , 1 DNA Way, South San Francisco, California 94080, United States.
authors: Wendy B
authors: WB
authors: Young
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D003545:Cysteine / Q000235:genetics*; D006801:Humans; D007700:Kinetics; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy; D009154:Mutation; D010880:Piperidines; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D011720:Pyrazoles / Q000627:therapeutic use; D011743:Pyrimidines / Q000627:therapeutic use; D013912:Threonine / Q000235:genetics*
chemical_list: D000970:Antineoplastic Agents; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; C551803:ibrutinib; D013912:Threonine; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; D000225:Adenine; D003545:Cysteine