Skyrun Pharma Co., Ltd.

Aberrant activation of fibroblast growth factor receptors (FGFRs) has been identified as an oncogenic driver force for multiple cancer types, making FGFRs a compelling target for anticancer therapy. Because of the renewed interest in irreversible inhibitors, considerable efforts have been made to find irreversible FGFR inhibitors. Herein, we discovered a series of novel quinolone-based covalent pan-FGFR inhibitors by further optimizing the lead compound (lenvatinib) under the guidance of molecular docking. The representative pan-FGFR inhibitor I-5 exhibited significant inhibitory potency against FGFR1-4 with nanomolar activity and effectively suppressed the proliferation of Huh-7 and Hep3B HCC cells. I-5 displayed high selectivity against a panel of 369 kinases at 1 μM. The irreversible binding to target proteins was characterized by liquid chromatography and tandem mass spectrometry (LC-MS/MS). Moreover, I-5 exhibited favorable PK properties in vivo and induced significant TGI in the Huh-7 and NCI-H1581 xenograft mouse models.

Monopolar spindle kinase 1 (Mps1) is a key element of the mitotic checkpoint and clinically evaluated as a target in the treatment of aggressive tumors. With this aim, a set of pyrazolo[3,4-b]pyridine-based compounds as new Mps1 inhibitors was investigated through a multidisciplinary approach, based on virtual screening, chemical synthesis and biological evaluation. One of the representative compounds, 31, exhibited strong kinase inhibitory potency against Mps1 with an IC₅₀ value of 2.596 nM and significantly inhibited proliferation of cancer cells, especially MDA-MB-468 and MV4-11 cells. Compound 31 also displayed reasonable kinome selectivity against a panel of 606 wild-type kinases at 1 μM. Moreover, compound 31 exhibited suitable preclinical pharmacokinetic parameters and a promising pharmacodynamic profile. Further, compound 31 showed good antitumor efficacy in MDA-MB-468 xenograft model with no obvious toxicity. Overall, compound 31 was identified as a potential Mps1 inhibitor for cancer therapy and deserve further research.

A formal aza-Michael addition and [4+3] annulation reactions of dichloro-substituted amides Cl₂CHC(O)NHOR¹ (R¹ = Me, Et, i-Pr, t-Bu, H₂C:CHCH₂, PhCH₂) with N-(2-chloromethyl)aryl amides I (R² = H, 4-MeO, 5-F, 5-Me, 5-Br, etc.; R³ = Me, i-Bu, PhCH₂) have been reported in this paper.The use of Cs₂CO₃ as a base exclusively gave the corresponding addition products II in good yields, which can be smoothly transformed into the formal [4+3] annulation products III if NaH is used as a base.The intriguing features of the aza-Michael addition/intramol. SN₂ domino reaction include their mild nature of the reaction conditions and easy handling for scalable synthesis.