Dataset Information

Discovery of Pyrazolopyrimidine Derivatives as Novel Dual Inhibitors of BTK and PI3K?.

ABSTRACT: The aberrant activation of B-cells has been implicated in several types of cancers and hematological disorders. BTK and PI3K? are kinases responsible for B-cell signal transduction, and inhibitors of these enzymes have demonstrated clinical benefit in certain types of lymphoma. Simultaneous inhibition of these pathways could result in more robust responses or overcome resistance as observed in single agent use. We report a series of novel compounds that have low nanomolar potency against both BTK and PI3K? as well as acceptable PK properties that could be useful in the development of treatments against B-cell related diseases.

SUBMITTER: Pujala B

PROVIDER: S-EPMC5150666 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Publications

Discovery of Pyrazolopyrimidine Derivatives as Novel Dual Inhibitors of BTK and PI3Kδ.

Pujala Brahmam B Agarwal Anil K AK Middya Sandip S Banerjee Monali M Surya Arjun A Nayak Anjan K AK Gupta Ashu A Khare Sweta S Guguloth Rambabu R Randive Nitin A NA Shinde Bharat U BU Thakur Anamika A Patel Dhananjay I DI Raja Mohd M Green Michael J MJ Alfaro Jennifer J Avila Patricio P Pérez de Arce Felipe F Almirez Ramona G RG Kanno Stacy S Bernales Sebastián S Hung David T DT Chakravarty Sarvajit S McCullagh Emma E Quinn Kevin P KP Rai Roopa R Pham Son M SM

ACS medicinal chemistry letters 20161028 12

The aberrant activation of B-cells has been implicated in several types of cancers and hematological disorders. BTK and PI3Kδ are kinases responsible for B-cell signal transduction, and inhibitors of these enzymes have demonstrated clinical benefit in certain types of lymphoma. Simultaneous inhibition of these pathways could result in more robust responses or overcome resistance as observed in single agent use. We report a series of novel compounds that have low nanomolar potency against both BT ...[more]

PMID: 27994757

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Project description:Activated B-cell-like diffuse large B-cell lymphoma relies on B-cell receptor signaling to drive proliferation and survival. Downstream of the B-cell receptor, the key signaling kinases Bruton's tyrosine kinase and phosphoinositide 3-kinase δ offer opportunities for therapeutic intervention by agents such as ibrutinib, ONO/GS-4059, and idelalisib. Combination therapy with such targeted agents could provide enhanced efficacy due to complimentary mechanisms of action. In this study, we describe both the additive interaction of and resistance mechanisms to idelalisib and ONO/GS-4059 in a model of activated B-cell-like diffuse large B-cell lymphoma. Significant tumor regression was observed with a combination of PI3Kδ and Bruton's tyrosine kinase inhibitors in the mouse TMD8 xenograft. Acquired resistance to idelalisib in the TMD8 cell line occurred by loss of phosphatase and tensin homolog and phosphoinositide 3-kinase pathway upregulation, but not by mutation of PIK3CD. Sensitivity to idelalisib could be restored by combining idelalisib and ONO/GS-4059. Further evaluation of targeted inhibitors revealed that the combination of idelalisib and the phosphoinositide-dependent kinase-1 inhibitor GSK2334470 or the AKT inhibitor MK-2206 could partially overcome resistance. Characterization of acquired Bruton's tyrosine kinase inhibitor resistance revealed a novel tumor necrosis factor alpha induced protein 3 mutation (TNFAIP3 Q143*), which led to a loss of A20 protein, and increased p-IκBα. The combination of idelalisib and ONO/GS-4059 partially restored sensitivity in this resistant line. Additionally, a mutation in Bruton's tyrosine kinase at C481F was identified as a mechanism of resistance. The combination activity observed with idelalisib and ONO/GS-4059, taken together with the ability to overcome resistance, could lead to a new therapeutic option in activated B-cell-like diffuse large B-cell lymphoma. A clinical trial is currently underway to evaluate the combination of idelalisib and ONO/GS-4059 (NCT02457598).

Dataset Information

Discovery of Pyrazolopyrimidine Derivatives as Novel Dual Inhibitors of BTK and PI3K?.

Publications

Discovery of Pyrazolopyrimidine Derivatives as Novel Dual Inhibitors of BTK and PI3Kδ.

Similar Datasets

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