Fig. 2

2100 compound small-molecule screening in isogenic models of dysregulated dynamics uncovers differential drug sensitivities. a Immunoblot of OPA1, Drp1, or a loading control in TYKNU cells transduced with a control CRISPR or three independent sgRNAs targeting either OPA1 or DNM1L. Immunoblots are cropped for clarity. Immunoblot is representative of three independent experiments. b Schematic of the small-molecule screening method. c Left, snake plot depicting the log₂(sgOPA1/sgCTRLA1) cellular viability ratio across 2100 compounds at two doses per compound. Right, snake plot depicting the log₂(sgDNM1L/sgCTRLA1) cellular viability ratio across 2100 compounds at two doses per compound. Blue indicates a sensitivity, red indicates a resistance. d A count of the number of hits in each of the conditions listed. e A plot showing the log₂(sgOPA1/sgCTRLA1) vs. the log₂(sgDNM1L/sgCTRLA1) cellular viability ratios across three classes of drugs involving autophagy, transmembrane transporters, and apoptosis. Red indicates a compound that passes the hit-calling threshold for at least one knockout derivative. f A plot showing the log₂(sgOPA1/sgCTRLA1) vs. the log₂(sgDNM1L/sgCTRLA1) cellular viability ratios for drugs targeting nucleotide metabolism. Red indicates drugs that target purine metabolism and blue indicates drugs that target pyrimidine metabolism. g A boxplot showing the log₂(knockout/control) cellular viability ratio for drugs that target guanine vs. those that target adenine. Data are mean ± SEM. *p < 0.05 by one-way ANOVA. h The log₂(mDivi-1 25 μM/vehicle) GI₅₀ for purine targeting drugs guanosine, penciclovir, adefovir dipivoxil, or pyrimidine targeting drugs, gemcitabine or 5-FU. Data are mean ± SEM. *p < 0.05 by one-way ANOVA. i GI₅₀ curves for guanosine, adefovir dipivoxil, and gemcitabine in TYKNU cells transduced with a control targeting sgRNA or three independent sgRNAs targeting either OPA1 or DNM1L (n = 3). Data are mean ± SEM. *p < 0.05 by one-way ANOVA