Our recent breakthrough discovery demonstrated that the anticancer drug FL118 tightly binds to and then dephosphorylates and degrades the oncogenic protein DEAD-box helicase 5(DDX5),leading to the inhibition of DDX5 d...Our recent breakthrough discovery demonstrated that the anticancer drug FL118 tightly binds to and then dephosphorylates and degrades the oncogenic protein DEAD-box helicase 5(DDX5),leading to the inhibition of DDX5 downstream targets(e.g.,survivin,myeloid cell leukemia 1(Mcl-1),X-linked inhibitor of apoptosis(XIAP),c-Myc,mutant Kras,etc.)[1].FL118 is a molecular glue(MG)that can alter the interactomes of two or more non-interacting proteins[2].Thus,FL118 exhibits high efficacy against colorectal and pancreatic cancer xenograft tumors[1,3].However,moving FL118 into clinical trials requires a clinically compatible FL118 drug product(DP)that possesses high antitumor efficacy and low toxicity via oral(ideal)or intravenous(iv)administration.Here,we report the development and characterization of a clinically and orally compatible FL118 DP.We show that(1)FL118 drug substances(DS)exhibit high chemical stability under various test conditions;(2)a clinically and orally compatible FL118 DP can be manufactured through the formulation of FL118 DS with 2-hydroxypropyl-bcyclodextrin(HPbCD)using mixed solvents of glacial acetic acid(GAA)with ethanol through microfluidizer-mediated spray dried dispersion(M-SDD).展开更多
文摘Our recent breakthrough discovery demonstrated that the anticancer drug FL118 tightly binds to and then dephosphorylates and degrades the oncogenic protein DEAD-box helicase 5(DDX5),leading to the inhibition of DDX5 downstream targets(e.g.,survivin,myeloid cell leukemia 1(Mcl-1),X-linked inhibitor of apoptosis(XIAP),c-Myc,mutant Kras,etc.)[1].FL118 is a molecular glue(MG)that can alter the interactomes of two or more non-interacting proteins[2].Thus,FL118 exhibits high efficacy against colorectal and pancreatic cancer xenograft tumors[1,3].However,moving FL118 into clinical trials requires a clinically compatible FL118 drug product(DP)that possesses high antitumor efficacy and low toxicity via oral(ideal)or intravenous(iv)administration.Here,we report the development and characterization of a clinically and orally compatible FL118 DP.We show that(1)FL118 drug substances(DS)exhibit high chemical stability under various test conditions;(2)a clinically and orally compatible FL118 DP can be manufactured through the formulation of FL118 DS with 2-hydroxypropyl-bcyclodextrin(HPbCD)using mixed solvents of glacial acetic acid(GAA)with ethanol through microfluidizer-mediated spray dried dispersion(M-SDD).
