title: Discovery of Pyrazolopyrimidine Derivatives as Novel Dual Inhibitors of BTK and PI3Kδ.
abstract: 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 BTK and PI3Kδ as well as acceptable PK properties that could be useful in the development of treatments against B-cell related diseases.
authors.affiliation: Integral BioSciences, Pvt. Ltd. , C-64, Hosiery Complex Phase II Extension, Noida, Uttar Pradesh 201306, India.
authors.forename: Brahmam
authors.initials: B
authors.lastname: Pujala
authors.affiliation: Integral BioSciences, Pvt. Ltd. , C-64, Hosiery Complex Phase II Extension, Noida, Uttar Pradesh 201306, India.
authors.forename: Anil K
authors.initials: AK
authors.lastname: Agarwal
authors.affiliation: Curadev, Pvt. Ltd. , B-87, Sector 83, Noida, Uttar Pradesh 201305, India.
authors.forename: Sandip
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authors.lastname: Middya
authors.affiliation: Curadev, Pvt. Ltd. , B-87, Sector 83, Noida, Uttar Pradesh 201305, India.
authors.forename: Monali
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authors.lastname: Banerjee
authors.affiliation: Curadev, Pvt. Ltd. , B-87, Sector 83, Noida, Uttar Pradesh 201305, India.
authors.forename: Arjun
authors.initials: A
authors.lastname: Surya
authors.affiliation: Integral BioSciences, Pvt. Ltd. , C-64, Hosiery Complex Phase II Extension, Noida, Uttar Pradesh 201306, India.
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authors.initials: AK
authors.lastname: Nayak
authors.affiliation: Integral BioSciences, Pvt. Ltd. , C-64, Hosiery Complex Phase II Extension, Noida, Uttar Pradesh 201306, India.
authors.forename: Ashu
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authors.lastname: Gupta
authors.affiliation: Integral BioSciences, Pvt. Ltd. , C-64, Hosiery Complex Phase II Extension, Noida, Uttar Pradesh 201306, India.
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authors.lastname: Khare
authors.affiliation: Integral BioSciences, Pvt. Ltd. , C-64, Hosiery Complex Phase II Extension, Noida, Uttar Pradesh 201306, India.
authors.forename: Rambabu
authors.initials: R
authors.lastname: Guguloth
authors.affiliation: Integral BioSciences, Pvt. Ltd. , C-64, Hosiery Complex Phase II Extension, Noida, Uttar Pradesh 201306, India.
authors.forename: Nitin A
authors.initials: NA
authors.lastname: Randive
authors.affiliation: Integral BioSciences, Pvt. Ltd. , C-64, Hosiery Complex Phase II Extension, Noida, Uttar Pradesh 201306, India.
authors.forename: Bharat U
authors.initials: BU
authors.lastname: Shinde
authors.affiliation: Integral BioSciences, Pvt. Ltd. , C-64, Hosiery Complex Phase II Extension, Noida, Uttar Pradesh 201306, India.
authors.forename: Anamika
authors.initials: A
authors.lastname: Thakur
authors.affiliation: Integral BioSciences, Pvt. Ltd. , C-64, Hosiery Complex Phase II Extension, Noida, Uttar Pradesh 201306, India.
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authors.initials: DI
authors.lastname: Patel
authors.affiliation: Integral BioSciences, Pvt. Ltd. , C-64, Hosiery Complex Phase II Extension, Noida, Uttar Pradesh 201306, India.
authors.forename: Mohd
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authors.lastname: Raja
authors.affiliation: Medivation, Inc. , 525 Market Street, 36th Floor, San Francisco, California 94105, United States.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Green
authors.affiliation: Fundación Ciencia y Vida , Avenida Zañartu 1482, Ñuñoa, Santiago 7780272, Chile.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Alfaro
authors.affiliation: Fundación Ciencia y Vida , Avenida Zañartu 1482, Ñuñoa, Santiago 7780272, Chile.
authors.forename: Patricio
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authors.lastname: Avila
authors.affiliation: Fundación Ciencia y Vida, Avenida Zañartu 1482, Ñuñoa, Santiago 7780272, Chile; Departamento de Ciencias Biológicas, Facultad de Ciencias Biológicas, Universidad Andrés Bello, Santiago 8370146, Chile.
authors.forename: Felipe
authors.initials: F
authors.lastname: Pérez de Arce
authors.affiliation: Medivation, Inc. , 525 Market Street, 36th Floor, San Francisco, California 94105, United States.
authors.forename: Ramona G
authors.initials: RG
authors.lastname: Almirez
authors.affiliation: Medivation, Inc. , 525 Market Street, 36th Floor, San Francisco, California 94105, United States.
authors.forename: Stacy
authors.initials: S
authors.lastname: Kanno
authors.affiliation: Medivation, Inc. , 525 Market Street, 36th Floor, San Francisco, California 94105, United States.
authors.forename: Sebastián
authors.initials: S
authors.lastname: Bernales
authors.affiliation: Medivation, Inc. , 525 Market Street, 36th Floor, San Francisco, California 94105, United States.
authors.forename: David T
authors.initials: DT
authors.lastname: Hung
authors.affiliation: Medivation, Inc. , 525 Market Street, 36th Floor, San Francisco, California 94105, United States.
authors.forename: Sarvajit
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authors.lastname: Chakravarty
authors.affiliation: Medivation, Inc. , 525 Market Street, 36th Floor, San Francisco, California 94105, United States.
authors.forename: Emma
authors.initials: E
authors.lastname: McCullagh
authors.affiliation: Medivation, Inc. , 525 Market Street, 36th Floor, San Francisco, California 94105, United States.
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Quinn
authors.affiliation: Medivation, Inc. , 525 Market Street, 36th Floor, San Francisco, California 94105, United States.
authors.forename: Roopa
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authors.lastname: Rai
authors.affiliation: Medivation, Inc. , 525 Market Street, 36th Floor, San Francisco, California 94105, United States.
authors.forename: Son M
authors.initials: SM
authors.lastname: Pham
keywords: B-cell; BCR; BTK; PI3K; inhibitor; p110δ; pyrazolopyrimidine