The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy

Honigberg, Lee; Smith, Ashley; Sirisawad, Mint; Verner, Erik; Loury, Dana N.; Chang, Betty; Li, Shyr; Pan, Zhengying; Thamm, Douglas H.; Miller, Richard A.; Buggy, Joseph J.

doi:10.1073/pnas.1004594107

Cited by 1,327 publications

(1,284 citation statements)

References 28 publications

(31 reference statements)

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“…28). Recent advances in identification of covalent kinase inhibitors based on acrylamide warheads [29][30][31][32][33] led us to design a prototypical reactomics library to explore the role of Cys residues in HIF-1a/ARNT PPI with the potential that the small fragments attached to the warhead could serve as a starting point for further development of selective covalent inhibitors or for design of non-covalent allosteric binders. Mass spec analysis of an iodoacetamide modified 1106 stability mutant indicated that both Cys255 and Cys337 sulfhydryl groups in the internal cavity could be accessed using acetamide chemistry, while probing with b-mercaptoethanol revealed slow reaction kinetics (data not shown).…”

Section: Discussionmentioning

confidence: 99%

Identification of Cys255 in HIF‐1α as a novel site for development of covalent inhibitors of HIF‐1α/ARNT PasB domain protein–protein interaction

et al. 2012

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The heterodimer HIF-1a (hypoxia inducible factor)/HIF-b (also known as ARNT-aryl hydrocarbon nuclear translocator) is a key mediator of cellular response to hypoxia. The interaction between these monomer units can be modified by the action of small molecules in the binding interface between their C-terminal heterodimerization (PasB) domains. Taking advantage of the presence of several cysteine residues located in the allosteric cavity of HIF-1a PasB domain, we applied a cysteine-based reactomics ''hotspot identification'' strategy to locate regions of HIF1a PasB domain critical for its interaction with ARNT. COMPOUND 5 was identified using a mass spectrometry-based primary screening strategy and was shown to react specifically with Cys255 of the HIF-1a PasB domain. Biophysical characterization of the interaction between PasB domains of HIF-1a and ARNT revealed that covalent binding of COMPOUND 5 to Cys255 reduced binding affinity between HIF-1a and ARNT PasB domains approximately 10-fold. Detailed NMR structural analysis of HIF-1a-PasB-COMPOUND 5 conjugate showed significant local conformation changes in the HIF-1a associated with key residues involved in the HIF-1a/ARNT PasB domain interaction as revealed by the crystal structure of the HIF-1a/ARNT PasB heterodimer. Our screening strategy could be applied to other targets to identify pockets surrounding reactive cysteines suitable for development of small molecule modulators of protein function.

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Section: Discussionmentioning

confidence: 99%

Identification of Cys255 in HIF‐1α as a novel site for development of covalent inhibitors of HIF‐1α/ARNT PasB domain protein–protein interaction

et al. 2012

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“…The TEC kinase inhibitor Ibrutinib (PCI-32765; ref. 35) was used to inhibit BMX (similar potency against Bruton's Tyrosine Kinase, its primary target). PI-103 and Ibrutinib were assessed in combination with ABT-737.…”

Section: Pi3k/bmx Pathway Inhibition Sensitized Sclc Cell Lines To Abmentioning

confidence: 99%

Inhibition of PI3K/BMX Cell Survival Pathway Sensitizes to BH3 Mimetics in SCLC

Potter

Galvin

Brown

et al. 2016

Molecular Cancer Therapeutics

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Most small cell lung cancer (SCLC) patients are initially responsive to cytotoxic chemotherapy, but almost all undergo fatal relapse with progressive disease, highlighting an urgent need for improved therapies and better patient outcomes in this disease. The proapoptotic BH3 mimetic ABT-737 that targets BCL-2 family proteins demonstrated good single-agent efficacy in preclinical SCLC models. However, so far clinical trials of the BH3 mimetic Navitoclax have been disappointing. We previously demonstrated that inhibition of a PI3K/BMX cell survival signaling pathway sensitized colorectal cancer cells to ABT-737. Here, we show that SCLC cell lines, which express high levels of BMX, become sensitized to ABT-737 upon inhibition of PI3K in vitro, and this is dependent on inhibition of the PI3K-BMX-AKT/mTOR signaling pathway. Consistent with these cell line data, when combined with Navitoclax, PI3K inhibition suppressed tumor growth in both an established SCLC xenograft model and in a newly established circulating tumor cell-derived explant (CDX) model generated from a blood sample obtained at presentation from a chemorefractory SCLC patient. These data show for the first time that a PI3K/BMX signaling pathway plays a role in SCLC cell survival and that a BH3 mimetic plus PI3K inhibition causes prolonged tumor regression in a chemorefractory SCLC patient-derived model in vivo. These data add to a body of evidence that this combination should move toward the clinic.

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“…The binding of the drug to these kinases is reversible. However, it is of importance that the affinity of binding for the proteins such as BRK, CSK, FRG and HCK is in the low nanomolar range, that is not very different from that of BTK 15. Another molecule with high binding affinity (IC 50 0.5 n m ) and ibrutinib binding site is BLK (Table 1).…”

Section: Introductionmentioning

confidence: 99%

Targets for Ibrutinib Beyond B Cell Malignancies

et al. 2015

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Ibrutinib (Imbruvica™) is an irreversible, potent inhibitor of Bruton's tyrosine kinase (BTK). Over the last few years, ibrutinib has developed from a promising drug candidate to being approved by FDA for the treatment of three B cell malignancies, a truly remarkable feat. Few, if any medicines are monospecific and ibrutinib is no exception; already during ibrutinib's initial characterization, it was found that it could bind also to other kinases. In this review, we discuss the implications of such interactions, which go beyond the selective effect on BTK in B cell malignancies. In certain cases, the outcome of ibrutinib treatment likely results from the combined inhibition of BTK and other kinases, causing additive or synergistic, effects. Conversely, there are also examples when the clinical outcome seems unrelated to inhibition of BTK. Thus, more specifically, adverse effects such as enhanced bleeding or arrhythmias could potentially be explained by different interactions. We also predict that during long‐term treatment bone homoeostasis might be affected due to the inhibition of osteoclasts. Moreover, the binding of ibrutinib to molecular targets other than BTK or effects on cells other than B cell‐derived malignancies could be beneficial and result in new indications for clinical applications.

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The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy

Cited by 1,327 publications

References 28 publications

Identification of Cys255 in HIF‐1α as a novel site for development of covalent inhibitors of HIF‐1α/ARNT PasB domain protein–protein interaction

Identification of Cys255 in HIF‐1α as a novel site for development of covalent inhibitors of HIF‐1α/ARNT PasB domain protein–protein interaction

Inhibition of PI3K/BMX Cell Survival Pathway Sensitizes to BH3 Mimetics in SCLC

Targets for Ibrutinib Beyond B Cell Malignancies

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