Fibrolamellar carcinoma (FLC) is a rare, difficult-to-treat liver cancer primarily affecting pediatric and adolescent patients. An analysis of FLC tumor samples shows that protein kinase A (PKA) alpha catalytic subunit (PRKACA) is a critical molecular event in FLC pathogenesis. In this article, we will introduce an orally active, highly selective, ATP-competitive PRKACA inhibitor, BLU2864. BLU2864 inhibits PRKACA kinase with an IC₅₀ of 0.3 nM. Additionally, BLU2864 shows anti-tumor activity. BLU2864 can be used in cancer and polycystic kidney disease research. In mIMCD3 cells, BLU2864 (40 nM and 200 nM; 5 d) inhibits forskolin-induced in vitro cystogenesis of mIMCD3 cells cultured in Matrigel by 72% and 100% at 40 and 200 nM concentrations, respectively. Additionally, BLU2864 inhibits ex vivo p-Ser133 CREB expression and cystogenesis. In Vivo, in Pkd1RC/RC mice, BLU2864 (oral gavage; 45 mg/kg; once daily; 5 d) suppresses kidney basal and total PKA activities by 74% and 87% at 3 hours and by 46% and 56% at 15 hours, respectively. Additionally, BLU2864-treated mice showed higher urine outputs at 15 weeks than the controls. And it shows renal basal and total PKA activities by 69% and 84% lower in the BLU2864-treated mice compared with controls. As a result, downregulation of PKA activity and BLU2864 inhibits many pro-proliferative pathways and were both protective in vivo. In Mice harboring FLC PDX tumors, BLU2864 (oral gavage; 30 mg/kg and 75 mg/kg; once daily; 34 d) reduces FLC tumor growth in vivo. As a result, it leads to tumor inhibitory growth by 48.5% (P=0.003) and by 45.3% (P=0.0005), respectively, at day 34. In summary, BLU2864 is a potent and highly selective PRKACA inhibitor. And, it shows potential for fibrolamellar carcinoma research.