ABSTRACT
Inhibition of TGFß signaling in concert with a checkpoint blockade has been shown to provide improved and durable antitumor immune response in mouse models. However, on-target adverse cardiovascular effects have limited the clinical use of TGFß receptor (TGFßR) inhibitors in cancer therapy. To restrict the activity of TGFßR inhibitors to tumor tissues and thereby widen the therapeutic index, a series of tumor-activated prodrugs of a selective small molecule TGFßR1 inhibitor 1 were prepared by appending 1 to a serine protease substrate and a half-life extension fatty acid carbon chain. The prodrugs were shown to be selectively metabolized in tumor tissues relative to the heart and blood and demonstrated a prolonged favorable increase in the tumor-to-heart ratio of the active drug in tissue distribution studies. Once-weekly administration of the most tissue-selective compound 10 provided anti-tumor efficacy comparable to the parent compound and reduced systemic exposure of the active drug.
Subject(s)
Antineoplastic Agents/therapeutic use , Neoplasms/drug therapy , Prodrugs/therapeutic use , Receptor, Transforming Growth Factor-beta Type I/antagonists & inhibitors , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/chemistry , Antineoplastic Agents/metabolism , Area Under Curve , Drug Stability , Female , Half-Life , Humans , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Molecular Structure , Myocardium/metabolism , Neoplasms/metabolism , Prodrugs/chemistry , Prodrugs/pharmacokinetics , Small Molecule Libraries/pharmacology , Tissue Distribution , Xenograft Model Antitumor AssaysABSTRACT
Leukocyte function-associated antigen-1 (LFA-1), also known as CD11a/CD18 or alpha(L)beta(2), belongs to the beta(2) integrin subfamily and is constitutively expressed on all leukocytes. The major ligands of LFA-1 include three intercellular adhesion molecules 1, 2, and 3 (ICAM 1, 2, and 3). The interactions between LFA-1 and the ICAMs are critical for cell adhesion, and preclinical animal studies and clinical data from the humanized anti-LFA-1 antibody efalizumab have provided proof-of-concept for LFA-1 as an immunological target. This article will detail the structure-activity relationships (SAR) leading to a novel second generation series of highly potent spirocyclic hydantoin antagonists of LFA-1. With significantly enhanced in vitro and ex vivo potency relative to our first clinical compound (1), as well as demonstrated in vivo activity and an acceptable pharmacokinetic and safety profile, 6-((5S,9R)-9-(4-cyanophenyl)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro-[4.4]nonan-7-yl)nicotinic acid (2e) was selected to advance into clinical trials.
Subject(s)
Hydantoins/pharmacokinetics , Immunologic Factors/chemistry , Lymphocyte Function-Associated Antigen-1/drug effects , Nicotinic Acids/pharmacokinetics , Humans , Hydantoins/pharmacology , Lymphocyte Function-Associated Antigen-1/chemistry , Lymphocyte Function-Associated Antigen-1/immunology , Nicotinic Acids/toxicity , Structure-Activity RelationshipABSTRACT
The synthesis and SAR of a series of pyrrolopyridazine MEK inhibitors are reported. Optimal activity was achieved by incorporation of a 4-phenoxyaniline substituent at C4 and an acylated amine at C6.
