ABSTRACT
Potent estrogen receptor ligands typically contain a phenolic hydrogen-bond donor. The indazole of the selective estrogen receptor degrader (SERD) ARN-810 is believed to mimic this. Disclosed herein is the discovery of ARN-810 analogs which lack this hydrogen-bond donor. These SERDs induced tumor regression in a tamoxifen-resistant breast cancer xenograft, demonstrating that the indazole NH is not necessary for robust ER-modulation and anti-tumor activity.
Subject(s)
Antineoplastic Agents/pharmacology , Cinnamates/pharmacology , Drug Resistance, Neoplasm/drug effects , Indazoles/pharmacology , Receptors, Estrogen/antagonists & inhibitors , Selective Estrogen Receptor Modulators/pharmacology , Tamoxifen/pharmacology , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Proliferation/drug effects , Cell Survival/drug effects , Cinnamates/chemical synthesis , Cinnamates/chemistry , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Female , Indazoles/chemical synthesis , Indazoles/chemistry , Mammary Neoplasms, Experimental/drug therapy , Mammary Neoplasms, Experimental/metabolism , Mammary Neoplasms, Experimental/pathology , Mice , Molecular Structure , Receptors, Estrogen/metabolism , Selective Estrogen Receptor Modulators/chemical synthesis , Selective Estrogen Receptor Modulators/chemistry , Structure-Activity Relationship , Tamoxifen/chemical synthesis , Tamoxifen/chemistryABSTRACT
ER-targeted therapeutics provide valuable treatment options for patients with ER+ breast cancer, however, current relapse and mortality rates emphasize the need for improved therapeutic strategies. The recent discovery of prevalent ESR1 mutations in relapsed tumors underscores a sustained reliance of advanced tumors on ERα signaling, and provides a strong rationale for continued targeting of ERα. Here we describe GDC-0810, a novel, non-steroidal, orally bioavailable selective ER downregulator (SERD), which was identified by prospectively optimizing ERα degradation, antagonism and pharmacokinetic properties. GDC-0810 induces a distinct ERα conformation, relative to that induced by currently approved therapeutics, suggesting a unique mechanism of action. GDC-0810 has robust in vitro and in vivo activity against a variety of human breast cancer cell lines and patient derived xenografts, including a tamoxifen-resistant model and those that harbor ERα mutations. GDC-0810 is currently being evaluated in Phase II clinical studies in women with ER+ breast cancer.
Subject(s)
Antineoplastic Agents/administration & dosage , Breast Neoplasms/drug therapy , Cinnamates/administration & dosage , Indazoles/administration & dosage , Receptors, Estrogen/administration & dosage , Animals , Cell Line, Tumor , Disease Models, Animal , Heterografts , Humans , Mice , Prospective Studies , Rats , Treatment OutcomeABSTRACT
Selective estrogen receptor degraders (SERDs) have shown promise for the treatment of ER+ breast cancer. Disclosed herein is the continued optimization of our indazole series of SERDs. Exploration of ER degradation and antagonism in vitro followed by in vivo antagonism and oral exposure culminated in the discovery of indazoles 47 and 56, which induce tumor regression in a tamoxifen-resistant breast cancer xenograft.
Subject(s)
Antineoplastic Agents/therapeutic use , Breast Neoplasms/drug therapy , Estrogen Receptor Antagonists/therapeutic use , Indazoles/therapeutic use , Tamoxifen/therapeutic use , Animals , Antineoplastic Agents/chemistry , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Cinnamates/therapeutic use , Drug Resistance, Neoplasm , Estrogen Receptor Antagonists/metabolism , Female , Indazoles/chemistry , Rats , Structure-Activity Relationship , Xenograft Model Antitumor AssaysABSTRACT
The Ras/RAF/MEK/ERK mitogen-activated protein kinase (MAPK) signaling pathway plays a central role in the regulation of cell growth, differentiation, and survival. Expression of mutant BRAF(V600E) results in constitutive activation of the MAPK pathway, which can lead to uncontrolled cellular growth. Herein, we describe an SAR optimization campaign around a series of quinazoline derived BRAF(V600E) inhibitors. In particular, the bioisosteric replacement of a metabolically sensitive tert-butyl group with fluorinated alkyl moieties is described. This effort led directly to the identification of a clinical candidate, compound 40 (CEP-32496). Compound 40 exhibits high potency against several BRAF(V600E)-dependent cell lines and selective cytotoxicity for tumor cell lines expressing mutant BRAF(V600E) versus those containing wild-type BRAF. Compound 40 also exhibits an excellent PK profile across multiple preclinical species. In addition, significant oral efficacy was observed in a 14-day BRAF(V600E)-dependent human Colo-205 tumor xenograft mouse model, upon dosing at 30 and 100 mg/kg BID.
Subject(s)
Isoxazoles/chemical synthesis , Phenylurea Compounds/chemical synthesis , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Quinazolines/chemical synthesis , Administration, Oral , Animals , Binding, Competitive , Cell Line, Tumor , Cell Proliferation/drug effects , Dogs , Drug Screening Assays, Antitumor , Female , Humans , Isoxazoles/pharmacokinetics , Isoxazoles/pharmacology , Macaca fascicularis , Male , Mice , Mice, Nude , Microsomes, Liver , Models, Molecular , Mutation , Neoplasm Transplantation , Phenylurea Compounds/pharmacokinetics , Phenylurea Compounds/pharmacology , Proto-Oncogene Proteins B-raf/genetics , Quinazolines/pharmacokinetics , Quinazolines/pharmacology , Rats , Rats, Sprague-Dawley , Stereoisomerism , Structure-Activity Relationship , Transplantation, HeterologousABSTRACT
Aryl phenyl ureas with a 4-quinazolinoxy substituent at the meta-position of the phenyl ring are potent inhibitors of mutant and wild type BRAF kinase. Compound 7 (1-(5-tert-butylisoxazol-3-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea hydrochloride) exhibits good pharmacokinetic properties in rat and mouse and is efficacious in a mouse tumor xenograft model following oral dosing.
Subject(s)
Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Proto-Oncogene Proteins B-raf/metabolism , Quinazolines/pharmacology , Urea/pharmacology , Animals , Dose-Response Relationship, Drug , Mice , Molecular Structure , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Quinazolines/chemical synthesis , Quinazolines/chemistry , Rats , Stereoisomerism , Structure-Activity Relationship , Tissue Distribution , Urea/analogs & derivatives , Urea/chemistry , Xenograft Model Antitumor AssaysABSTRACT
Treatment of AML patients with small molecule inhibitors of FLT3 kinase has been explored as a viable therapy. However, these agents are found to be less than optimal for the treatment of AML because of lack of sufficient potency or suboptimal oral pharmacokinetics (PK) or lack of adequate tolerability at efficacious doses. We have developed a series of extremely potent and highly selective FLT3 inhibitors with good oral PK properties. The first series of compounds represented by 1 (AB530) was found to be a potent and selective FLT3 kinase inhibitor with good PK properties. The aqueous solubility and oral PK properties at higher doses in rodents were found to be less than optimal for clinical development. A novel series of compounds were designed lacking the carboxamide group of 1 with an added water solubilizing group. Compound 7 (AC220) was identified from this series to be the most potent and selective FLT3 inhibitor with good pharmaceutical properties, excellent PK profile, and superior efficacy and tolerability in tumor xenograft models. Compound 7 has demonstrated a desirable safety and PK profile in humans and is currently in phase II clinical trials.
Subject(s)
Benzothiazoles/pharmacology , Phenylurea Compounds/pharmacology , Protein Kinase Inhibitors/pharmacology , fms-Like Tyrosine Kinase 3/antagonists & inhibitors , Animals , Benzothiazoles/chemical synthesis , Benzothiazoles/chemistry , Benzothiazoles/pharmacokinetics , Cell Line, Tumor , Drug Evaluation, Preclinical , Female , Humans , Male , Mice , Phenylurea Compounds/chemical synthesis , Phenylurea Compounds/chemistry , Phenylurea Compounds/pharmacokinetics , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacokinetics , Rats , Solubility , Substrate Specificity , Xenograft Model Antitumor AssaysABSTRACT
A series of diaryl ureas with an amide substitution at the 4-position was prepared and found to be potent and selective FLT3 inhibitors with good oral bioavailability and efficacy in a tumor xenograft model.
Subject(s)
Antineoplastic Agents/chemistry , Urea/analogs & derivatives , fms-Like Tyrosine Kinase 3/antagonists & inhibitors , Administration, Oral , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacokinetics , Cell Line, Tumor , Humans , Mice , Mice, Nude , Structure-Activity Relationship , Urea/chemical synthesis , Urea/pharmacokinetics , Xenograft Model Antitumor Assays , fms-Like Tyrosine Kinase 3/metabolismABSTRACT
Kinase inhibitors show great promise as a new class of therapeutics. Here we describe an efficient way to determine kinase inhibitor specificity by measuring binding of small molecules to the ATP site of kinases. We have profiled 20 kinase inhibitors, including 16 that are approved drugs or in clinical development, against a panel of 119 protein kinases. We find that specificity varies widely and is not strongly correlated with chemical structure or the identity of the intended target. Many novel interactions were identified, including tight binding of the p38 inhibitor BIRB-796 to an imatinib-resistant variant of the ABL kinase, and binding of imatinib to the SRC-family kinase LCK. We also show that mutations in the epidermal growth factor receptor (EGFR) found in gefitinib-responsive patients do not affect the binding affinity of gefitinib or erlotinib. Our results represent a systematic small molecule-protein interaction map for clinical compounds across a large number of related proteins.
