Additional file 1 of MC180295 is a highly potent and selective CDK9 inhibitor with preclinical in vitro and in vivo efficacy in cancer
Creators: name: Zhang, Hanghang
name: Huang, Chen
name: Gordon, John
name: Yu, Sijia
name: Morton, George
name: Childers, Wayne
name: Abou-Gharbia, Magid
name: Zhang, Yi
name: Jelinek, Jaroslav
name: Issa, Jean-Pierre J.
Publisher: name: figshare
Year: 2024
Subjects: subject: Biophysics
subject: Biochemistry
subject: Cell Biology
subject: Genetics
subject: FOS: Biological sciences
subject: Molecular Biology
subject: Pharmacology
subject: Biotechnology
subject: Chemical Sciences not elsewhere classified
subject: Immunology
subject: FOS: Clinical medicine
subject: Biological Sciences not elsewhere classified
subject: Cancer
subject: Hematology
subject: Infectious Diseases
subject: FOS: Health sciences

description: Additional file 1: Fig. S1. MC180295 cancer cell growth inhibition and mouse pharmacokinetics. A Quantification of MC180295 IC50 values, against 46 cell lines from six cancer types, from Fig. 1A. B Time course of MC180295 plasma levels after 2.5 mg/kg oral or 1 mg/kg IV administration to mice. C Time course of MC180295 plasma levels after IP 10 mg/kg MC180295 administration to mice. D Time course of MC180295 plasma levels after 1 mg/kg MC180295 IV dosing of rats. Fig. S2. Epigenetic activity of MC180295. Re-expression of GFP (measured by a Cytation Imaging Reader), 4 days after single-dose treatment of YB5 reporter cells with MC180379, MC180380, and MC180295. Data are shown as means ± SDs, n = 3. ***p &lt; 0.001. Fig. S3. Blood cell effects and solubility of the MC180379 and MC180380 enantiomers. A Absolute neutrophil, lymphocyte and monocyte counts were determined by a complete blood cell counter after SW48 model mice were treated with either MC180379 or MC180380. B Absolute platelet counts were determined by a complete blood cell counter after SW48 model mice were treated with either MC180379 or MC180380. C Absolute neutrophil, lymphocyte, and monocyte counts after HT29 model mice were treated with either vehicle, MC180379, or MC180380. D Absolute platelet counts after HT29 model mice were treated with vehicle, MC180379, or MC180380. E In vitro activity (IC50, in nM) of MC180295, and its two enantiomers, against CDK9. F In vitro drug solubility assay comparing MC180379 with MC180380 in PBS. Data are shown as means ± SEMs (A, B, C) or SDs (D) (Student’s t test). *p &lt; 0.05, **p &lt; 0.01, ***p &lt; 0.001. Fig. S4. Toxicity of MC180295, MC180380, or their combination with DAC, in SW48 mice. A Absolute platelet counts were determined by a complete blood cell counter after SW48 model mice were treated with vehicle, MC180295, or DAC + MC180295. Data are shown as means ± SEMs. B Absolute neutrophil, lymphocyte, and monocyte counts, determined by a complete blood cell counter, after SW48 model mouse i.p. treatment with vehicle, MC180295, or MC180295 + DAC. C In the i.p. SW48 mouse model, MC180295 or MC180295 + DAC treatment did not affect NSG mouse body weights. D In the i.p. MV4-11 mouse model, DAC, MC180295, or MC180295 + DAC treatment did not affect NSG mouse body weights. E In the i.p. SW48 mouse model, MC180380 or MC180380 + DAC treatment did not affect NSG mouse body weights. F Absolute platelet counts after SW48 model mice were treated with vehicle, MC180380 or MC180380 + DAC. G Absolute neutrophil, lymphocyte, and monocyte counts after SW48 model mice were treated with vehicle, MC180380, or MC180380 + DAC. Data are shown as means ± SEMs (Student’s t test). *p &lt; 0.05. Fig. S5. Toxicity and antitumor effects of MC180295, DAC, or their combination, in CT26.CL25 mice. A In the i.p. CT26.CL25 immunocompetent mouse model, neither MC180295 nor MC180295 + DAC treatment affected NSG mouse body weights. B In the i.p. CT26.CL25 immunocompetent mice, neither MC180295 nor MC180295 + DAC treatment affected NSG mouse body weights, after CD8 depletion. C Antitumor effects of MC180295 and MC180295 + DAC. B6 mice were inoculated (s.c.) with 5 × 105 CT26.CL25 cells. Eight days later, when tumors were palpable, 20 mg/kg MC180295 was administered (i.p.) q.o.d. 0.5 mg/kg DAC was administered (i.p.) daily. Tumor sizes were measured using a caliper. D Antitumor effects of MC180295 and MC180295 + DAC after CD8 + T cell depletion via an anti-CD8 antibody. B6 mice were inoculated (s.c.) with 5 × 105 CT26.CL25 cells. Eight days later, when tumors were palpable, 20 mg/kg MC180295 was administered (i.p.) q.o.d. 0.5 mg/kg DAC was administered (i.p.) daily. Tumor sizes were measured using a caliper. E Absolute platelet counts were determined by a complete blood cell counter after mice were treated with vehicle, MC180295, or MC180295 + DAC in the CT26.CL25 immunocompetent mouse model, in the presence or absence of CD8 + T cells. F Absolute neutrophil, lymphocyte, and monocyte counts were determined by a complete blood cell counter after mice were treated with vehicle, MC180295, or DAC + MC180295, in CT26.CL25 immunocompetent mice. G Absolute neutrophil, lymphocyte, and monocyte counts after mice were treated with vehicle, MC180295, or DAC + MC180295 in CT26.CL25 immunocompetent mice, after CD8 depletion. Data are shown as means ± SEMs