2,4,6-Triaminopyrimidine as a Novel Hinge Binder in a Series of PI3Kδ Selective Inhibitors

Abstract

Inhibition of phosphoinositide 3-kinase δ (PI3Kδ) is an appealing target for several hematological malignancies and inflammatory diseases. Herein, we describe the discovery and optimization of a series of propeller shaped PI3Kδ inhibitors comprising a novel triaminopyrimidine hinge binder. Combinations of electronic and structural strategies were employed to mitigate aldehyde oxidase mediated metabolism. This medicinal chemistry effort culminated in the identification of 52, a potent and highly selective inhibitor of PI3Kδ that demonstrates efficacy in a rat model of arthritis.

Structural Determinants of Isoform Selectivity in PI3K Inhibitors

“…Combining this with an 8-chloro substitution in 13 restores selectivity to >100x. In a similar series reported by Patel et al [101] (Table 2), a 6-F substitution ( 15 ) has a limited effect on δ/α selectivity. 5-halogen substituents ( 16 ) show improvement in PI3Kδ potency and selectivity compared with an unsubstituted ring.…”

“…The authors hypothesize that a double interaction with both δLys779 and δAsp787 could compensate for the energy cost needed to open the specificity pocket in PI3Kα [107]. However, in a series of pyrrolotriazinone propeller shaped compounds, a pyrazole moiety in the affinity pocket ( 22 ) forms a triple interaction with the conserved δAsp787, δLys779 and δAsp911 (PDB ID 5I6U) and maintains good selectivity over PI3Kα (Figure 4e) [101].…”

“…Like the affinity pocket, the hinge residues are conserved between the four isoforms. 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].…”

Dose-Dependent Suppression of Cytokine production from T cells by a Novel Phosphoinositide 3-Kinase Delta Inhibitor

“…Biochemical potency of Compound A (referred as Compound 18 by Patel et al .) is 0.4 nM, and selectivity is 200x or better against the other 3 isoforms 28 . When Th17 cells were differentiated from total OT-II splenocytes and treated with this compound on day three of differentiation, the compound resulted in a potent, dose-dependent inhibition of IL-17 production upon CD3/CD28 stimulation.…”

Introduction of pyrrolidineoxy or piperidineamino group at the 4-position of quinazoline leading to novel quinazoline-based phosphoinositide 3-kinase delta (PI3Kδ) inhibitors

“…Duvelisib (Compound 2 ), another potent PI3Kδ inhibitor, shared chemical similarity to idelalisib, however, this was recently terminated in the phase III clinical trials due to underneath efficiency. Many other analogues derived from the chemical structure of idelalisib were recently reported and showed strong PI3Kδ efficacy and selectivity, for instances Compounds 3 (PI3Kδ: half maximal inhibitory concentration (IC 50 ) = 2.2 nM), 4 (PI3Kδ: IC 50 = 1.0 nM), and 5 (PI3Kδ: IC 50 = 4.6 nM) 9–11 . Nevertheless, our drug discovery efforts are engaged into the development of PI3Kδ inhibitors with novel and distinct chemotypes.…”