Thieno[3,2-d]pyrimidine derivatives 25(Korea University)

Being a primary driver in oncogenic activations of JAK-STAT signaling pathway, Janus Kinase 1 (JAK1) stands out as a promising target in anti-cancer drug discovery. We employed a scaffold morphing strategy to design and synthesize thieno[3,2-d]pyrimidine derivatives, which led to identification of 24 as a potent and highly selective JAK1 inhibitor. Kinome-wide selectivity profiling reveals that 24 exhibits a high degree of selectivity for JAK1 among the 370 kinases tested. SAR study demonstrates that both 25 and 46, improved derivatives of 24, possess higher selectivity towards JAK1 over JAK2 and JAK3 compared to AZD4205 (9). It is of note that 46 has 4-fold higher enzymatic activity against JAK1 (IC₅₀ = 0.022 μM) relative to 9. Moreover, both 25 and 46 demonstrate over 5-fold enhancement in anti-proliferative activities on NSCLC cells with regard to 9, accompanied by significant inhibition of JAK1 signaling. Compared with 9, derivative 24, 25, and 46 induce more strongly apoptosis, cell cycle arrest, and reduction of colony formation on NSCLC cells. Our findings offer valuable insights into the design of novel selective JAK1 inhibitors.

The concomitant inhibition of PI3Kδ and bromodomain and extra-terminal (BET) that exerts a synergistic effect on the B-cell receptor signaling pathway provides a new strategy for the treatment of aggressive diffuse large B-cell lymphoma (DLBCL). Herein, a merged pharmacophore strategy was utilized to discover a series of thieno[3,2-d]pyrimidine derivatives as the first-in-class bifunctional PI3Kδ-BET inhibitors. Through optimization, a highly potent compound (10b) was identified to possess excellent and balanced activities against PI3Kδ [inhibitory concentration (IC₅₀) = 112 ± 8 nM] and BRD4-BD1 (IC₅₀ = 19 ± 1 nM) and exhibited strong antiproliferative activities in DLBCL cells. Notably, this compound demonstrated good PI3Kδ selectivity over other kinases with minimal cytotoxicity in normal cells. Moreover, 10b has a good oral pharmacokinetic profile in mice and achieves outstanding antitumor activity in the SU-DHL-6 xenograft model. Taken together, these results indicate that targeting PI3Kδ and BET with a bifunctional inhibitor is a promising strategy to treat DLBCL.