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. 2016 Oct 28;7(12):1161-1166.
doi: 10.1021/acsmedchemlett.6b00356. eCollection 2016 Dec 8.

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

Brahmam Pujala  1 , Anil K Agarwal  1 , Sandip Middya  2 , Monali Banerjee  2 , Arjun Surya  2 , Anjan K Nayak  1 , Ashu Gupta  1 , Sweta Khare  1 , Rambabu Guguloth  1 , Nitin A Randive  1 , Bharat U Shinde  1 , Anamika Thakur  1 , Dhananjay I Patel  1 , Mohd Raja  1 , Michael J Green  3 , Jennifer Alfaro  4 , Patricio Avila  4 , Felipe Pérez de Arce  5 , Ramona G Almirez  3 , Stacy Kanno  3 , Sebastián Bernales  3 , David T Hung  3 , Sarvajit Chakravarty  3 , Emma McCullagh  3 , Kevin P Quinn  3 , Roopa Rai  3 , Son M Pham  3
Affiliations

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

Brahmam Pujala et al. ACS Med Chem Lett. .

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.

Keywords: B-cell; BCR; BTK; PI3K; inhibitor; p110δ; pyrazolopyrimidine.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Structural similarities between PCI-29732 and SW13.
Figure 2
Figure 2
Docking of PCI-29732 (A) and an overlay of SW13 (B) to BTK (3GEN) using Glide. The bound ligand is removed for ease of viewing.
Scheme 1
Scheme 1
Reagents and conditions: (a) 3-fluoro-5-methoxyphenylboronic acid (4), Na2CO3, Pd(PPh3)4, DMF, H2O, 75 °C, 2 h, 32%; (b) i. NaH, DMF, 0 °C-RT, ii. R-OMs, 80 °C, 2 h, 5–50%; (c) 1 M BBr3 in CH2Cl2, 0 °C, 18 h, 3–50%.
Scheme 2
Scheme 2
Reagents and conditions: (a) i. NaH, DMF, 0 °C-RT, ii. 12, 80 °C, 2 h, 51%; (b) Ar–B(OR)2, Na2CO3, Pd(PPh3)4, DMF, H2O, 75 °C, 2–3 h, 30–70%.
Figure 3
Figure 3
Docked poses of 27 (A) and 32 (B) with BTK indicate that 32 makes an additional H-bond interaction with Asn484.
See this image and copyright information in PMC

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