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Title: Battling Btk Mutants With Noncovalent Inhibitors That Overcome Cys481 and Thr474 Mutations

Journal Article · · ACS Chemical Biology
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  1. Genentech, San Francisco, CA (United States)
  2. Discovery Oncology, Genentech, 1 DNA Way, South San Francisco, California 94080, United States
+ Show Author Affiliations

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.

Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Organization:
USDOE Office of Science (SC), Basic Energy Sciences (BES)
Grant/Contract Number:
AC02-06CH11357
OSTI ID:
1347790
Journal Information:
ACS Chemical Biology, Vol. 11, Issue 10; ISSN 1554-8929
Publisher:
American Chemical Society (ACS)Copyright Statement
Country of Publication:
United States
Language:
ENGLISH
Citation Metrics:
Cited by: 84 works
Citation information provided by
Web of Science

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Cited By (14)

Water molecules in protein–ligand interfaces. Evaluation of software tools and SAR comparison journal February 2019
Covalent Inhibition in Drug Discovery journal March 2019
A non‐covalent inhibitor XMU‐MP‐3 overrides ibrutinib‐resistant Btk C481S mutation in B‐cell malignancies journal December 2019
Pharmacophore modeling and virtual screening in search of novel Bruton’s tyrosine kinase inhibitors journal June 2019
Enhancing intracellular accumulation and target engagement of PROTACs with reversible covalent chemistry journal August 2020
Ibrutinib in the management of Waldenstrom macroglobulinemia journal September 2017
Noncovalent inhibitors reveal BTK gatekeeper and auto-inhibitory residues that control its transforming activity journal June 2019
Targeting BTK in CLL: Beyond Ibrutinib journal April 2019
Bruton tyrosine kinase degradation as a therapeutic strategy for cancer journal February 2019
Ability of Bruton’s Tyrosine Kinase Inhibitors to Sequester Y551 and Prevent Phosphorylation Determines Potency for Inhibition of Fc Receptor but not B-Cell Receptor Signaling journal January 2017
Development of BTK inhibitors for the treatment of B-cell malignancies journal January 2019
Discovery of Potent and Selective Tricyclic Inhibitors of Bruton’s Tyrosine Kinase with Improved Druglike Properties journal May 2017
First-in-human phase 1 study of the BTK inhibitor GDC-0853 in relapsed or refractory B-cell NHL and CLL journal January 2018
Overcoming Ibrutinib Resistance in Chronic Lymphocytic Leukemia journal November 2019

Figures / Tables (10)

Table 1(p. 28)table Table 1
Table 2(p. 29)table Table 2
Figure 1(p. 30)figure Figure 1
Figure 2(p. 31)figure Figure 2
Figure 3(p. 32)figure Figure 3
Figure 4(p. 33)figure Figure 4
Figure 5a(p. 34)figure Figure 5a
Figure 5b(p. 35)figure Figure 5b
Figure 5c(p. 36)figure Figure 5c
Figure 6(p. 37)figure Figure 6

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