Discovery of Potent, Efficient, and Selective Inhibitors of Phosphoinositide 3-Kinase δ through a Deconstruction and Regrowth Approach

Barton, Nick; Convery, M.A.; Cooper, Anthony W. J.; Down, Kenneth; Hamblin, J. Nicole; Inglis, Graham G. A.; Peace, Simon; Rowedder, James E.; Rowland, Paul; Taylor, Jonathan A.; Wellaway, Natalie

doi:10.1021/acs.jmedchem.8b01556

Cited by 11 publications

(23 citation statements)

References 27 publications

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“…Co-crystal structures of inhibitors with p110δ catalytic subunit of PI3Kδ (such as PDB 4XE0, 6Q74) are available. Extensive SAR and pharmacokinetic profile exploration of different chemical series in comparison to PI3Kδ inhibitor Idelalisib approved for various malignancies, provides starting chemical space for novel drug design with a decent safety profile ( 94 , 96 ). Linker substitutions targeting the hydrophobic specificity pocket (formed by Trp760, Pro758 and Met752), along with optimization of hinge binder moiety ( Figure 4B ), is being proposed here as a promising approach for improvements in on-target and in vitro ADME profile.…”

Section: Drug Targets From Omics Approachesmentioning

confidence: 99%

New Druggable Targets for Rheumatoid Arthritis Based on Insights From Synovial Biology

Sandhu

Thelma

2022

Front. Immunol.

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Rheumatoid arthritis (RA) is a multifactorial autoimmune disease characterized by chronic inflammation and destruction of multiple small joints which may lead to systemic complications. Altered immunity via pathogenic autoantibodies pre-date clinical symptom development by several years. Incompletely understood range of mechanisms trigger joint-homing, leading to clinically evident articular disease. Advances in therapeutic approaches and understanding pathogenesis have improved prognosis and likely remission. However, partial/non-response to conventional and biologic therapies witnessed in a subset of patients highlights the need for new therapeutics. It is now evident that joint disease chronicity stems from recalcitrant inflammatory synovial environment, majorly maintained by epigenetically and metabolically reprogrammed synoviocytes. Therefore, interference with effector functions of activated cell types seems a rational strategy to reinstate synovial homeostasis and complement existing anti-inflammatory interventions to mitigate chronic RA. Presenting this newer aspect of fibroblast-like synoviocytes and myeloid cells underlying the altered synovial biology in RA and its potential for identification of new druggable targets is attempted in this review. Major leads from i) molecular insights of pathogenic cell types from hypothesis free OMICS approaches; ii) hierarchy of their dysregulated signaling pathways; and iii) knowledge of druggability of molecular nodes in these pathways are highlighted. Development of such synovial biology-directed therapeutics hold promise for an enriched drug repertoire for RA.

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Section: Drug Targets From Omics Approachesmentioning

confidence: 99%

New Druggable Targets for Rheumatoid Arthritis Based on Insights From Synovial Biology

Sandhu

Thelma

2022

Front. Immunol.

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“…Modification of the hinge-binder of duvelisib from the purine ring to the 4-amino,5-cyano-pyrimidine 28 was able to increase selectivity for PI3Kδ from 55-1200x to 200-4600x (Figure 5) [101]. A recent paper from GSK have investigated the combination of a pyridine sulfonamide, which they describe as a privileged PI3Kδ fragment, with a series of hinge binding moieties ( 29 , Figure 5) [109]. They observe marked differences in isoform selectivity that is dependent on the hinge binding moiety.…”

Section: Structural Determinants Of Isoform Selectivitymentioning

confidence: 99%

“…Bulky substitutions at the 4-position of a quinoline specificity pocket binding motif ( 42 ) explore the tryptophan shelf from the specificity pocket (PDB ID 5KAE) (Figure 8) [119,120]. A recent paper from GSK have described a novel binding mode for PI3Kδ inhibitors (see compound 29 ), that involves a “conformational switch” of δTrp760 (Figure 5) [109]. The conformation of δTrp760 flips, such that the indole nitrogen is available to hydrogen bond with inhibitor functional groups that sit at the tryptophan shelf.…”

Section: Structural Determinants Of Isoform Selectivitymentioning

confidence: 99%

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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“…Let us now consider the role of the sulphone group for the ligand-Chk1 interactions. The sulphone or sulphonamide functionality is frequently present in the anticancer molecules where they act as hydrogen bond acceptors from amino acids with pendent amino or hydroxy groups often in the kinases domains [41][42][43]. Moreover, the sulphone functionality often works as an important spacer for kinase inhibitors [44].…”

Section: Ligand Dockingmentioning

confidence: 99%

Selected arylsulphonyl pyrazole derivatives as potential Chk1 kinase ligands—computational investigations

et al. 2020

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Protein kinases control diversity of biochemical processes in human organism. Checkpoint 1 kinase (Chk1) is an important element of the checkpoint signalling pathways and is responsible for DNA damage repair. Hence, this kinase plays an essential role in cancer cells survival and has become an important target for anticancer agents. Our previous investigations showed that some arylsulphonyl indazole derivatives displayed anticancer effect in vitro. In the present study, in order to verify possibility of interactions of pyrazole and indazole derivatives with Chk1, we focused on the docking of selected tosyl derivatives of indazole and condensed pyrazole 1–7 to the Chk1 pocket, analysis of interactions involving optimized ligand–protein system using DFT formalism, and estimation of the interaction enthalpy of the ligand–protein complex by applying the PM7 method. The estimation of binding affinity seems to indicate that the indazole 5-substituted with 3,5-dimethylpyrazole 4 and condensed pyrazoloquinoline derivative 7 fit the best to the Chk1-binding pocket. The values of the energy of interaction, i.e. the enthalpy change (ΔHint), were between − 85.06 and − 124.04 kcal mol−1 for the optimized ligand–Chk1 complexes. The relaxation of the ligands within the complexes azole–protein as well as the distribution of hydrogen contacts between the ligands and kinase pocket amino acids was also analysed using molecular dynamics as a supporting method.

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Discovery of Potent, Efficient, and Selective Inhibitors of Phosphoinositide 3-Kinase δ through a Deconstruction and Regrowth Approach

Cited by 11 publications

References 27 publications

New Druggable Targets for Rheumatoid Arthritis Based on Insights From Synovial Biology

New Druggable Targets for Rheumatoid Arthritis Based on Insights From Synovial Biology

Structural Determinants of Isoform Selectivity in PI3K Inhibitors

Selected arylsulphonyl pyrazole derivatives as potential Chk1 kinase ligands—computational investigations

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