Design, synthesis and prostate cancer cell-based studies of analogs of the Rho/MKL1 transcriptional pathway inhibitor, CCG-1423.
We recently identified bis(amide) CCG-1423 (1) as a novel inhibitor of RhoA/C-mediated gene transcription that is capable of inhibiting invasion of PC-3 prostate cancer cells in a Matrigel model of metastasis. An initial structure-activity relationship study focusing on bioisosteric replacement of the amides and conformational restriction identified two compounds, 4g and 8, with improved selectivity for inhibition of RhoA/C-mediated gene transcription and attenuated cytotoxicity relative to 1. Both compounds were also capable of inhibiting cell invasion with equal efficacy to 1 but with less attendant cytotoxicity.
Evelyn
Chris R
CR
Department of Pharmacology, University of Michigan Medical School, University of Michigan, Ann Arbor, MI 48109, USA.
Bell
Jessica L
JL
Ryu
Jenny G
JG
Wade
Susan M
SM
Kocab
Andrew
A
Harzdorf
Nicole L
NL
Showalter
H D
HD
Neubig
Richard R
RR
Larsen
Scott D
SD
D000813:Anilides / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D000814:Aniline Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D001549:Benzamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D006801:Humans; D008297:Male; D009361:Neoplasm Invasiveness; D015514:Oncogene Proteins, Fusion / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D011471:Prostatic Neoplasms / Q000188:drug therapy; D013329:Structure-Activity Relationship; D015534:Trans-Activators; D014158:Transcription, Genetic; D020742:rhoA GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
D000813:Anilides; D000814:Aniline Compounds; D001549:Benzamides; C523455:CCG 1423; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; C431575:MRTFA protein, human; D015514:Oncogene Proteins, Fusion; D010880:Piperidines; D015534:Trans-Activators; D020742:rhoA GTP-Binding Protein