ABSTRACT
The further optimization of ER-α degradation efficacy of a series of ER modulators by refining side-chain substitution led to efficacious selective estrogen receptor degraders (SERDs). A fluoromethyl azetidine group was found to be preferred and resulted in the identification of bis-phenol chromene 17ha. In a tamoxifen-resistant breast cancer xenograft model, 17ha (ER-α degradation efficacy = 97%) demonstrated tumor regression, together with robust reduction of intratumoral ER-α levels. However, despite superior oral exposure, 5a (ER-α degradation efficacy = 91%) had inferior activity. This result suggests that optimizing ER-α degradation efficacy leads to compounds with robust effects in a model of tamoxifen-resistant breast cancer. Compound 17ha (GDC-0927) was evaluated in clinical trials in women with metastatic estrogen receptor-positive breast cancer.
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
About 75% of breast cancers are estrogen receptor alpha (ER-α) positive, and women typically initially respond well to antihormonal therapies such as tamoxifen and aromatase inhibitors, but resistance often emerges. Fulvestrant is a steroid-based, selective estrogen receptor degrader (SERD) that both antagonizes and degrades ER-α and shows some activity in patients who have progressed on antihormonal agents. However, fulvestrant must be administered by intramuscular injections that limit its efficacy. We describe the optimization of ER-α degradation efficacy of a chromene series of ER modulators resulting in highly potent and efficacious SERDs such as 14n. When examined in a xenograft model of tamoxifen-resistant breast cancer, 14n (ER-α degradation efficacy = 91%) demonstrated robust activity, while, despite superior oral exposure, 15g (ER-α degradation efficacy = 82%) was essentially inactive. This result suggests that optimizing ER-α degradation efficacy in the MCF-7 cell line leads to compounds with robust effects in models of tamoxifen-resistant breast cancer derived from an MCF-7 background.
Subject(s)
Antineoplastic Agents/administration & dosage , Benzopyrans/chemistry , Breast Neoplasms/drug therapy , Cell Proliferation/drug effects , Estrogen Receptor alpha/metabolism , Selective Estrogen Receptor Modulators/administration & dosage , Administration, Oral , Animals , Antineoplastic Agents/chemistry , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Drug Resistance, Neoplasm/drug effects , Female , Humans , Mice , Rats , Selective Estrogen Receptor Modulators/chemistry , Tumor Cells, Cultured , Xenograft Model Antitumor AssaysABSTRACT
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
Approximately 80% of breast cancers are estrogen receptor alpha (ER-α) positive, and although women typically initially respond well to antihormonal therapies such as tamoxifen and aromatase inhibitors, resistance often emerges. Although a variety of resistance mechanism may be at play in this state, there is evidence that in many cases the ER still plays a central role, including mutations in the ER leading to constitutively active receptor. Fulvestrant is a steroid-based, selective estrogen receptor degrader (SERD) that both antagonizes and degrades ER-α and is active in patients who have progressed on antihormonal agents. However, fulvestrant suffers from poor pharmaceutical properties and must be administered by intramuscular injections that limit the total amount of drug that can be administered and hence lead to the potential for incomplete receptor blockade. We describe the identification and characterization of a series of small-molecule, orally bioavailable SERDs which are potent antagonists and degraders of ER-α and in which the ER-α degrading properties were prospectively optimized. The lead compound 11l (GDC-0810 or ARN-810) demonstrates robust activity in models of tamoxifen-sensitive and tamoxifen-resistant breast cancer, and is currently in clinical trials in women with locally advanced or metastatic estrogen receptor-positive breast cancer.
Subject(s)
Antineoplastic Agents/therapeutic use , Breast Neoplasms/drug therapy , Estrogen Receptor alpha/metabolism , Proteolysis/drug effects , Selective Estrogen Receptor Modulators/pharmacology , Small Molecule Libraries/therapeutic use , Tamoxifen/pharmacology , Administration, Oral , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacokinetics , Breast/drug effects , Breast/metabolism , Breast/pathology , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Cell Line, Tumor , Dogs , Drug Discovery , Drug Resistance, Neoplasm/drug effects , Female , Heterografts , Humans , Mice , Rats , Small Molecule Libraries/administration & dosage , Small Molecule Libraries/chemistry , Small Molecule Libraries/pharmacokineticsABSTRACT
Accelerated proliferation of solid tumor and hematologic cancer cells is linked to accelerated transcription of rDNA by the RNA polymerase I (Pol I) enzyme to produce elevated levels of rRNA (rRNA). Indeed, upregulation of Pol I, frequently caused by mutational alterations among tumor suppressors and oncogenes, is required for maintenance of the cancer phenotype and forms the basis for seeking selective inhibitors of Pol I as anticancer therapeutics. 2-(4-Methyl-[1,4]diazepan-1-yl)-5-oxo-5H-7-thia-1,11b-diaza-benzo[c]fluorene-6-carboxylic acid (5-methyl-pyrazin-2-ylmethyl)-amide (CX-5461, 7c) has been identified as the first potent, selective, and orally bioavailable inhibitor of RNA Pol I transcription with in vivo activity in tumor growth efficacy models. The preclinical data support the development of CX-5461 as an anticancer drug with potential for activity in several types of cancer.
ABSTRACT
In this article we describe the preclinical characterization of 5-(3-chlorophenylamino) benzo[c][2,6]naphthyridine-8-carboxylic acid (CX-4945), the first orally available small molecule inhibitor of protein CK2 in clinical trials for cancer. CX-4945 was optimized as an ATP-competitive inhibitor of the CK2 holoenzyme (Ki = 0.38 nM). Iterative synthesis and screening of analogs, guided by molecular modeling, led to the discovery of orally available CX-4945. CK2 promotes signaling in the Akt pathway and CX-4945 suppresses the phosphorylation of Akt as well as other key downstream mediators of the pathway such as p21. CX-4945 induced apoptosis and caused cell cycle arrest in cancer cells in vitro. CX-4945 exhibited a dose-dependent antitumor activity in a xenograft model of PC3 prostate cancer model and was well tolerated. In vivo time-dependent reduction in the phosphorylation of the biomarker p21 at T145 was observed by immunohistochemistry. Inhibition of the newly validated CK2 target by CX-4945 represents a fresh therapeutic strategy for cancer.
Subject(s)
Casein Kinase II/antagonists & inhibitors , Naphthyridines/therapeutic use , Prostatic Neoplasms/drug therapy , Protein Kinase Inhibitors/therapeutic use , Small Molecule Libraries/therapeutic use , Xenograft Model Antitumor Assays , Administration, Oral , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Casein Kinase II/metabolism , Caspase 3/metabolism , Caspase 7/metabolism , Cell Cycle/drug effects , Cell Line, Tumor , Humans , Immunohistochemistry , Male , Mice , Naphthyridines/chemistry , Naphthyridines/pharmacology , Phenazines , Phosphorylation/drug effects , Prostatic Neoplasms/enzymology , Prostatic Neoplasms/pathology , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Small Molecule Libraries/administration & dosage , Small Molecule Libraries/chemistry , Small Molecule Libraries/pharmacology , Structure-Activity RelationshipABSTRACT
Herein we chronicle the discovery of CX-4945 (25n), a first-in-class, orally bioavailable ATP-competitive inhibitor of protein kinase CK2 in clinical trials for cancer. CK2 has long been considered a prime cancer drug target because of the roles of deregulated and overexpressed CK2 in cancer-promoting prosurvival and antiapoptotic pathways. These biological properties as well as the suitability of CK2's small ATP binding site for the design of selective inhibitors, led us to fashion novel therapeutic agents for cancer. The optimization leading to 25n (K(i) = 0.38 nM) was guided by molecular modeling, suggesting a strong binding of 25n resulting from a combination of hydrophobic interactions, an ionic bridge with Lys68, and hydrogen bonding with the hinge region. 25n was found to be highly selective, orally bioavailable across species (20-51%) and efficacious in xenograft models. The discovery of 25n will allow the therapeutic targeting of CK2 in humans for the first time.
Subject(s)
Antineoplastic Agents/chemical synthesis , Casein Kinase II/antagonists & inhibitors , Naphthyridines/chemical synthesis , Adenosine Triphosphate/metabolism , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Binding, Competitive , Biological Availability , Cell Line, Tumor , Dogs , Drug Screening Assays, Antitumor , Humans , Hydrogen Bonding , Hydrophobic and Hydrophilic Interactions , Mice , Mice, Inbred ICR , Mice, Nude , Models, Molecular , Naphthyridines/chemistry , Naphthyridines/pharmacology , Neoplasm Transplantation , Phenazines , Rats , Structure-Activity Relationship , Transplantation, HeterologousABSTRACT
SAR studies on the quinolone carboxylic acid class of HIV-1 integrase inhibitors focused on improving the metabolic stability and led to the discovery of 27 and 38.
Subject(s)
HIV Integrase Inhibitors/metabolism , HIV Integrase Inhibitors/pharmacology , HIV-1/enzymology , Microsomes, Liver/metabolism , Quinolines/metabolism , Quinolines/pharmacology , Animals , Dogs , HIV Infections/drug therapy , HIV Integrase Inhibitors/chemistry , HIV Integrase Inhibitors/pharmacokinetics , Haplorhini , Humans , Naphthyridines/chemistry , Naphthyridines/metabolism , Naphthyridines/pharmacokinetics , Naphthyridines/pharmacology , Quinolines/chemistry , Quinolines/pharmacokinetics , Rats , Structure-Activity RelationshipABSTRACT
This letter details the attenuation of hERG in a class of Akt inhibitors through heteroatom insertions into aromatic rings. The development of a cell-active dual Akt 1 and 2 inhibitors devoid of hERG activity is discussed using structure-activity relationships.
Subject(s)
Enzyme Inhibitors/pharmacology , Ether-A-Go-Go Potassium Channels/chemistry , Proto-Oncogene Proteins c-akt/antagonists & inhibitors , Allosteric Regulation , Allosteric Site , Chemistry, Pharmaceutical/methods , Drug Design , ERG1 Potassium Channel , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Ether-A-Go-Go Potassium Channels/metabolism , Humans , Inhibitory Concentration 50 , Models, Chemical , Structure-Activity RelationshipABSTRACT
Structure-activity relationship studies leading to the discovery of novel mGlu5 receptor antagonists are described. These compounds show high in vitro potency, have good in vivo receptor occupancy, and a reasonable intravenous pharmacokinetic profile.
Subject(s)
Excitatory Amino Acid Antagonists/pharmacology , Pyridines/pharmacology , Receptors, Metabotropic Glutamate/antagonists & inhibitors , Excitatory Amino Acid Antagonists/pharmacokinetics , Pyridines/pharmacokinetics , Receptor, Metabotropic Glutamate 5ABSTRACT
Pyrimidine methyl anilines as potent and selective mGlu2 potentiators are described. Findings from the structure-activity-relationship investigations are discussed.