Discovery of Pyrazoloquinazoline Analogues as Orally Bioavailable KRAS-G12D Inhibitors

G12D is a dominant mutant of KRAS, accounting for 67.6% of PDAC cases, which drives the development of selective KRAS-G12D inhibitors in cancer therapy. Herein, we describe the rationale design, synthesis, and biological evaluation of KRAS-G12D inhibitors with pyrazoloquinazoline and 3,5-ethylene-bridged piperazine groups as the key pharmacophores. Compound <b>53a</b> exhibited comparable binding to KRAS-G12D (Δ<i>T</i>_m = 12.1 °C) and potent in vitro activities (IC₅₀ values of 8.4 nM and 19.5 nM against p-ERK and proliferation of AsPC-1 cells, respectively), compared to those of MRTX1133 as a reference standard. Furthermore, compound <b>53a</b> displayed appreciable plasma exposure, bioavailability, and pharmacokinetic profiles after oral administration, overcoming the poor oral bioavailability observed in MRTX1133. In vivo study showed that <b>53a</b> significantly inhibited tumor growth in the AsPC-1 xenograft mouse model by inhibiting KRAS-G12D. These findings support <b>53a</b> as a promising lead candidate for the development of selective KRAS-G12D targeted cancer therapies.