Discovery of a Pyrimidinedione Derivative as a Potent and Orally Bioavailable Axl Inhibitor

Abstract

The receptor tyrosine kinase Axl plays important roles in promoting cancer progression, metastasis, and drug resistance and has been identified as a promising target for anticancer therapeutics. We used molecular modeling-assisted structural optimization starting with the low micromolar potency compound 9 to discover compound 13c, a highly potent and orally bioavailable Axl inhibitor. Selectivity profiling showed that 13c could inhibit the well-known oncogenic kinase Met with equal potency to its inhibition of Axl superfamily kinases. Compound 13c significantly inhibited cellular Axl and Met signaling, suppressed Axl- and Met-driven cell proliferation, and restrained Gas6/Axl-mediated cancer cell migration or invasion. Furthermore, 13c exhibited significant antitumor efficacy in Axl-driven and Met-driven tumor xenograft models, causing tumor stasis or regression at well-tolerated doses. All these favorable data make 13c a promising therapeutic candidate for cancer treatment.

Umpolung Synthesis of Pyridyl Ethers by BiV‐Mediated O‐Arylation of Pyridones

“…Crucially, however, the Bi‐mediated arylation methodology is highly effective for electron‐rich pyridyl partners ( 12 , 24 , 33 ), which are traditionally challenging to engage in S N Ar. For example, the 4‐alkoxy substructure of 12 and 24 is accessed in only modest yields at >110 °C via S N Ar [39] or at 130 °C under Cu catalysis, [40] whereas aminopyridines analogous to 33 are accessible via S N Ar only at very high temperatures (140–220 °C) [41–43] . These results highlight the valuable complementarity that results from the opposing electronic demands of our method and S N Ar.…”

“…For example, the 4-alkoxy substructure of 12 and 24 is accessed in only modest yields at >110 °C via SNAr [39] or at 130 °C under Cu catalysis, [40] whereas aminopyridines analogous to 33 are accessible via SNAr only at very high temperatures (140-220 °C). [41][42] [43] These results highlight the valuable complementarity that results from the opposing electronic demands of our method and SNAr. The scope with respect to the boronic acid arylating agent is similarly broad.…”

Bio-engineered nano-vesicles for IR820 delivery: a therapy platform for cancer by surgery and photothermal therapy

“…39,40 Here, we selected the natural Axl-binding molecules Gas6 as the targeting protein. 41,42 Through the genetic engineering method, the targeting protein was designed and expressed on HEK293T cell membranes by coupling with the signal peptide and transmembrane peptide (Table S1 and Fig. 1A, S3 and S4 †).…”

“…As a proof-of-principle, Axl (Anexelekto) is a membrane receptor of the Tyro-Axl-Mer receptor tyrosine kinase (RTK) family, which can specifically bind to the Gas6 ligand. [38][39][40][41][42] Importantly, overexpression of Axl in HCC is closely related to a lower 5-year survival rate of patients due to drug resistance in targeted therapy or chemotherapy. 43 Unfortunately, Axl-overexpressing HCC accounts for 43.0% (230/535) of HCC.…”

Discovery of AXL Degraders with Improved Potencies in Triple-Negative Breast Cancer (TNBC) Cells

“…The synthesis of compound 10a−10l has been described in the literature. 30 2-Bromo-N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4yl)acetamide (10a). Yield, 78%.…”