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1.
Bioorg Med Chem Lett ; 50: 128335, 2021 10 15.
Article in English | MEDLINE | ID: mdl-34425201

ABSTRACT

Fulvestrant is an FDA-approved drug with a dual mechanism of action (MOA), acting as a full antagonist and degrader of the estrogen receptor protein. A significant limitation of fulvestrant is the dosing regimen required for efficacy. Due to its high lipophilicity and poor pharmacokinetic profile, fulvestrant needs to be administered through intramuscular injections which leads to injection site soreness. This route of administration also limits the dose and target occupancy in patients. We envisioned a best-in-class molecule that would function with the same dual MOA as fulvestrant, but with improved physicochemical properties and would be orally bioavailable. Herein we report our progress toward that goal, resulting in a new lead GNE-502 which addressed some of the liabilities of our previously reported lead molecule GNE-149.


Subject(s)
Antineoplastic Agents/pharmacology , Antineoplastic Agents/pharmacokinetics , Breast Neoplasms/drug therapy , Drug Discovery , Receptors, Estrogen/metabolism , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/chemistry , Dose-Response Relationship, Drug , Female , Humans , MCF-7 Cells , Mice , Molecular Structure , Protein Conformation , Xenograft Model Antitumor Assays
2.
J Med Chem ; 64(16): 11841-11856, 2021 08 26.
Article in English | MEDLINE | ID: mdl-34251202

ABSTRACT

Breast cancer remains a leading cause of cancer death in women, representing a significant unmet medical need. Here, we disclose our discovery efforts culminating in a clinical candidate, 35 (GDC-9545 or giredestrant). 35 is an efficient and potent selective estrogen receptor degrader (SERD) and a full antagonist, which translates into better antiproliferation activity than known SERDs (1, 6, 7, and 9) across multiple cell lines. Fine-tuning the physiochemical properties enabled once daily oral dosing of 35 in preclinical species and humans. 35 exhibits low drug-drug interaction liability and demonstrates excellent in vitro and in vivo safety profiles. At low doses, 35 induces tumor regressions either as a single agent or in combination with a CDK4/6 inhibitor in an ESR1Y537S mutant PDX or a wild-type ERα tumor model. Currently, 35 is being evaluated in Phase III clinical trials.


Subject(s)
Antineoplastic Agents/therapeutic use , Breast Neoplasms/drug therapy , Carbolines/therapeutic use , Estrogen Receptor Antagonists/therapeutic use , Estrogen Receptor alpha/metabolism , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacokinetics , Carbolines/chemistry , Carbolines/pharmacokinetics , Dogs , Estrogen Receptor Antagonists/chemistry , Estrogen Receptor Antagonists/pharmacokinetics , Female , Humans , MCF-7 Cells , Macaca fascicularis , Mice , Molecular Structure , Rats , Structure-Activity Relationship , Xenograft Model Antitumor Assays
3.
ACS Med Chem Lett ; 11(6): 1342-1347, 2020 Jun 11.
Article in English | MEDLINE | ID: mdl-32551022

ABSTRACT

Estrogen receptor alpha (ERα) is a well-validated drug target for ER-positive (ER+) breast cancer. Fulvestrant is FDA-approved to treat ER+ breast cancer and works through two mechanisms-as a full antagonist and selective estrogen receptor degrader (SERD)-but lacks oral bioavailability. Thus, we envisioned a "best-in-class" molecule with the same dual mechanisms as fulvestrant, but with significant oral exposure. Through lead optimization, we discovered a tool molecule 12 (GNE-149) with improved degradation and antiproliferative activity in both MCF7 and T47D cells. To illustrate the binding mode and key interactions of this scaffold with ERα, we obtained a cocrystal structure of 6 that showed ionic interaction of azetidine with Asp351 residue. Importantly, 12 showed favorable metabolic stability and good oral exposure. 12 exhibited antagonist effect in the uterus and demonstrated robust dose-dependent efficacy in xenograft models.

4.
Bioorg Med Chem Lett ; 29(16): 2090-2093, 2019 08 15.
Article in English | MEDLINE | ID: mdl-31311734

ABSTRACT

Phenolic groups are responsible for the high clearance and low oral bioavailability of the estrogen receptor alpha (ERα) clinical candidate GDC-0927. An exhaustive search for a backup molecule with improved pharmacokinetic (PK) properties identified several metabolically stable analogs, although in general at the expense of the desired potency and degradation efficiency. C-8 hydroxychromene 30 is the first example of a phenol-containing chromene that not only maintained excellent potency but also exhibited 10-fold higher oral exposure in rats. The improved in vivo clearance in rat was hypothesized to be the result of C-8 hydroxy group being sterically protected from glucuronide conjugation. The excellent potency underscores the possibility of replacing the presumed indispensable phenolic group at C-6 or C-7 of the chromene core. Co-crystal structures were obtained to highlight the change in key interactions and rationalize the retained potency.


Subject(s)
Azetidines/pharmacology , Estrogen Receptor alpha/metabolism , Flavonoids/pharmacology , Administration, Oral , Animals , Azetidines/administration & dosage , Azetidines/metabolism , Azetidines/pharmacokinetics , Crystallography, X-Ray , Drug Discovery , Drug Stability , Flavonoids/administration & dosage , Flavonoids/metabolism , Flavonoids/pharmacokinetics , Humans , MCF-7 Cells , Microsomes, Liver/metabolism , Rats , Stereoisomerism , Structure-Activity Relationship
5.
Bioorg Med Chem Lett ; 17(2): 363-9, 2007 Jan 15.
Article in English | MEDLINE | ID: mdl-17107790

ABSTRACT

Further investigation of a series of thienyl-based hydroxamic acids that included ADS100380 and ADS102550 led to the identification of the 5-pyridin-2-yl-thiophene-2-hydroxamic acid 3c, which possessed modest HDAC inhibitory activity. Substitution at the 5- and 6-positions of the pyridyl ring of compound 3c provided compounds 5a-g, 7a, b, 9, and 13a. Compound 5b demonstrated improved potency, in vitro DMPK profile, and rat oral bioavailability, compared to ADS102550. Functionalisation of the pendent phenyl group of compounds 5b, 5e and 13a provided analogues that possessed excellent enzyme inhibition and anti-proliferative activity.


Subject(s)
Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Histone Deacetylase Inhibitors , Hydroxamic Acids/chemical synthesis , Hydroxamic Acids/pharmacology , Thiophenes/chemical synthesis , Thiophenes/pharmacology , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Biological Availability , Caco-2 Cells , Cell Line, Tumor , Cell Proliferation/drug effects , Cytochrome P-450 CYP3A , Cytochrome P-450 Enzyme Inhibitors , Enzyme Inhibitors/pharmacokinetics , Humans , Indicators and Reagents , Injections, Intravenous , Mice , Microsomes, Liver/drug effects , Microsomes, Liver/enzymology , Microsomes, Liver/metabolism , Rats , Structure-Activity Relationship
6.
Bioorg Med Chem Lett ; 17(2): 370-5, 2007 Jan 15.
Article in English | MEDLINE | ID: mdl-17095213

ABSTRACT

Optimisation of ADS100380, a sub-micromolar HDAC inhibitor identified using a virtual screening approach, led to a series of substituted 5-(1H-pyrazol-3-yl)-thiophene-2-hydroxamic acids (6a-i), that possessed significant HDAC inhibitory activity. Subsequent functionalisation of the pendent phenyl group of compounds 6f and 6g provided analogues 6j-w with further enhanced enzyme and anti-proliferative activity. Compound 6j demonstrated efficacy in a mouse xenograft experiment.


Subject(s)
Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Histone Deacetylase Inhibitors , Hydroxamic Acids/chemical synthesis , Hydroxamic Acids/pharmacology , Pyrazoles/chemical synthesis , Pyrazoles/pharmacology , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Biological Availability , Cell Line, Tumor , Cell Proliferation/drug effects , Computer Simulation , Drug Evaluation, Preclinical , Enzyme Inhibitors/pharmacokinetics , Humans , Indicators and Reagents , Mice , Neoplasm Transplantation , Neoplasms, Experimental/drug therapy , Rats , Structure-Activity Relationship , Transplantation, Heterologous
7.
Bioorg Med Chem ; 10(3): 759-68, 2002 Mar.
Article in English | MEDLINE | ID: mdl-11814866

ABSTRACT

Three different routes for the synthesis of heterocyclic analogues of the second messenger D-myo-inositol-1,4,5-trisphosphate (InsP(3)) and the natural adenophostins, starting from allyl D-xyloside are described. The two diastereoisomers at C-2 of new compounds, which we named xylophostins, were obtained. The preliminary biological studies shows that the presence of the adenine residue has a beneficial effect on the affinity for the receptor. The low potency of one of the two diastereoisomeric compounds shows that the configuration of the carbon bearing the non-vicinal phosphate group is an important requirement for a high affinity to the receptor. These results provide evidence for the existence of a binding pocket for the adenine ring nearby the InsP(3) binding site. The consequence of these stabilizing interactions should be to place the phosphate group in a suitable position to perfectly mimic InsP(3) in the more active diastereoisomer. Obviously, in the other diastereoisomer, the phosphate cannot accommodate the same orientation, thus explaining the low affinity. The existence of such a binding pocket for adenine is in line with the high potency of adenophostins.


Subject(s)
Adenosine/analogs & derivatives , Adenosine/chemical synthesis , Calcium Channel Agonists/chemical synthesis , Inositol 1,4,5-Trisphosphate/chemical synthesis , Adenosine/chemistry , Adenosine/pharmacology , Animals , Binding Sites , Binding, Competitive , Calcium Channel Agonists/chemistry , Calcium Channel Agonists/pharmacology , Calcium Channels/chemistry , Calcium Channels/metabolism , Hepatocytes/metabolism , Inositol 1,4,5-Trisphosphate/chemistry , Inositol 1,4,5-Trisphosphate/pharmacology , Inositol 1,4,5-Trisphosphate Receptors , Microsomes , Molecular Conformation , Molecular Mimicry , Phosphates/chemistry , Rats , Receptors, Cytoplasmic and Nuclear/antagonists & inhibitors , Receptors, Cytoplasmic and Nuclear/chemistry , Receptors, Cytoplasmic and Nuclear/metabolism , Second Messenger Systems/drug effects , Structure-Activity Relationship
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