Discovery of pyrazolopyrimidine derivatives as potent BTK inhibitors with effective anticancer activity in MCL

Recent developments in anticancer kinase inhibitors based on the pyrazolo[3,4-d]pyrimidine scaffold

“…Analysis of pyrazolo [3,4-d]pyrimidine BTK inhibitors identifies some common characteristics; a northern region at the C3-position of the central core that exploits a hydrophobic pocket, the central core itself, and the Michael acceptor warhead, which is attached to the core at the N1position by a linker. 49 Several studies have focussed on the warhead and have swapped the α,β-unsaturated carbonyl moiety in favour of more reactive groups such as chloroacetyl groups (Fig. 4).…”

“…This compound maintained BTK-potency relative to 3, and kinome profiling demonstrated a greater selectivity for BTK over a range of kinases, including EGFR. 49 Optimisation of 9 sought to modify the phenyl rings in the C3-position of the molecule through the addition of pyridine rings in the linker to improve binding. Although most of the new derivatives were weakly potent for BTK, 10, which incorporated a chloroacetyl warhead, demonstrated a lownanomolar potency against BTK, with improved anticancer activity in a Mantle cell lymphoma cell line and improved selectivity over other kinases.…”

The Development of BTK Inhibitors: A Five-Year Update

“…Among these compounds, derivative 16 ( Figure 7 ) exhibited potent BTK inhibition (IC 50 = 27 nM), high selectivity, antiproliferative effects in primary patient tumor cells, and strong apoptosis induction in Jeko-1 and Z138 cells. Specifically, 16 showed antiproliferative activities in MCL cell lines with IC 50 values lower than 1 μM [ 87 ].…”

Design and synthesis of novel pyrazolopyrimidine-based derivatives as reversible BTK inhibitors with potent antiproliferative activity in mantle cell lymphoma

“…In previous studies, a reversible BTK inhibitor 9 exhibited moderate inhibitory activity against BTK (IC 50 = 0.23 μM) and low antiproliferative activity in MCL cells. 17 In this work, we performed further structural modi cations for compound 9 to improve its antiproliferative activity. It has been reported that optimization of the linker and terminal groups in the BTK inhibitors stands a potential strategy to improve its anti-tumor activity.…”

“…It has been reported that optimization of the linker and terminal groups in the BTK inhibitors stands a potential strategy to improve its anti-tumor activity. [17][18][19] Based on these, we retained the backbone and hydrophobic groups of lead compound 9, extended the linker and introduced diverse substituents (single, multiple, electronwithdrawing, or electron-donating) on the terminal benzene ring for additional interactions with the amino acid residues around the solvent region. In this way, a series of 3-(4-phenoxyphenyl)-1H-pyrazolo [3,4d]pyrimidin-4-amine-based derivatives are designed (Figure 2).…”