Discovery of 7-(3-(piperazin-1-yl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine derivatives as highly potent and selective PI3Kδ inhibitors

Qin, Lan-Ying; Ruan, Zheming; Cherney, Robert J.; Dhar, T. G. Murali; Neels, James; Weigelt, Carolyn A.; Sack, John S.; Srivastava, Anurag S.; Cornelius, Lyndon; Tino, Joseph A.; Stefanski, Kevin; Gu, Xiaomei; Xie, Jenny; Susulic, Vojkan; Yang, Xiaoxia; Yarde-Chinn, Melissa; Skala, Stacey; Bosnius, Ruth; Goldstein, Christine; Davies, Paul; Ruepp, Stefan; Salter–Cid, Luisa; Bhide, Rajeev S.; Poss, Michael A.

doi:10.1016/j.bmcl.2017.01.016

Cited by 15 publications

(12 citation statements)

References 18 publications

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“…From the same team of researchers, another PI3Kδ inhibitor, 42 , with higher activity and selectivity over β isoform than 41 was reported (Fig. 17 ) [ 131 ]. The cellular activity (B-cells) of 42 (IC 50 = 5.8 nM) was slightly better than 41 .…”

Section: Serine/threonine Kinase Inhibitorsmentioning

confidence: 99%

Pyrrolo[2,1-f][1,2,4]triazine: a promising fused heterocycle to target kinases in cancer therapy

2021

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Section: Serine/threonine Kinase Inhibitorsmentioning

confidence: 99%

Pyrrolo[2,1-f][1,2,4]triazine: a promising fused heterocycle to target kinases in cancer therapy

2021

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“…A total of 46 PI3Kδ structures have been deposited into the PDB (as of 25 January 2019). In addition to the murine ΔABD-p110δ structure, human p110δ/iSH2 structures have also been published (PDB ID 5T8F, 5UBT, 5VLR), with lower resolution than the ΔABD structures (2.8–2.9 Å) [93,94,95].…”

Section: Structural Biology Of Pi3kmentioning

confidence: 99%

“…To give further insight into how these families of inhibitors achieve their selectivity, crystal structures of the same inhibitor have been determined in two isoforms [94,108,116]. The crystal structure of the quinazoline-based inhibitor 39 in p110δ (PDB ID 5IS5) reveals that the acetyl-piperazine group of the ligand stacks with δTrp760 using the tryptophan shelf (Figure 7a) [116].…”

Section: Structural Determinants Of Isoform Selectivitymentioning

confidence: 99%

“…A follow up paper describes further development of this series of inhibitors to optimize the conformation and hydrophobic interactions with δTrp760 [75]. Conversely, a similar set of p110α (PDB ID 5UBR) and p110δ (PDB ID 5UBT) structures show that the pyrrolo-triazine inhibitor 40 , binds to p110α and p110δ in the same conformation (Figure 7b) [94,117]. In p110δ, the acetylpiperazinyl moiety sits at the tryptophan shelf, and the acyl group forms a hydrogen bond with the hydroxyl from δThr750.…”

Section: Structural Determinants Of Isoform Selectivitymentioning

confidence: 99%

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Structural Determinants of Isoform Selectivity in PI3K Inhibitors

Miller

Thompson²,

Gabelli

2019

Biomolecules

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Phosphatidylinositol 3-kinases (PI3Ks) are important therapeutic targets for the treatment of cancer, thrombosis, and inflammatory and immune diseases. The four highly homologous Class I isoforms, PI3K, PI3K, PI3K and PI3K have unique, non-redundant physiological roles and as such, isoform selectivity has been a key consideration driving inhibitor design and development. In this review, we discuss the structural biology of PI3Ks and how our growing knowledge of structure has influenced the medicinal chemistry of PI3K inhibitors. We present an analysis of the available structure-selectivity-activity relationship data to highlight key insights into how the various regions of the PI3K binding site influence isoform selectivity. The picture that emerges is one that is far from simple and emphasizes the complex nature of protein-inhibitor binding, involving protein flexibility, energetics, water networks and interactions with non-conserved residues.

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“…Pyrrolotriazine 2 was recently reported as a very potent PI3Kδ inhibitor (Figure 2). 12 Despite excellent potency in a CD69 human whole blood (hWB) assay, this molecule lacked selectivity over PI3Kα and PI3Kγ. Furthermore, its high polar surface area (PSA = 124 Å 2 ) resulted in poor in vitro ADME properties.…”

Section: ■ Chemistrymentioning

confidence: 99%

Identification of a Potent, Selective, and Efficacious Phosphatidylinositol 3-Kinase δ (PI3Kδ) Inhibitor for the Treatment of Immunological Disorders

et al. 2017

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PI3Kδ plays an important role controlling immune cell function and has therefore been identified as a potential target for the treatment of immunological disorders. This article highlights our work toward the identification of a potent, selective, and efficacious PI3Kδ inhibitor. Through careful SAR, the successful replacement of a polar pyrazole group by a simple chloro or trifluoromethyl group led to improved Caco-2 permeability, reduced Caco-2 efflux, reduced hERG PC activity, and increased selectivity profile while maintaining potency in the CD69 hWB assay. The optimization of the aryl substitution then identified a 4'-CN group that improved the human/rodent correlation in microsomal metabolic stability. Our lead molecule is very potent in PK/PD assays and highly efficacious in a mouse collagen-induced arthritis model.

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Discovery of 7-(3-(piperazin-1-yl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine derivatives as highly potent and selective PI3Kδ inhibitors

Cited by 15 publications

References 18 publications

Pyrrolo[2,1-f][1,2,4]triazine: a promising fused heterocycle to target kinases in cancer therapy

Pyrrolo[2,1-f][1,2,4]triazine: a promising fused heterocycle to target kinases in cancer therapy

Structural Determinants of Isoform Selectivity in PI3K Inhibitors

Identification of a Potent, Selective, and Efficacious Phosphatidylinositol 3-Kinase δ (PI3Kδ) Inhibitor for the Treatment of Immunological Disorders

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