Peter Rix

Launch Bioscience, Inc.

Background Cannabidiol (CBD), a non-psychoactive cannabinoid with a low toxicity profile, has been shown to produce antitumor activity across cancers in part through selective production of reactive oxygen species (ROS) in tumor cells. The alkylating agent, temozolomide (TMZ), is standard of care for treatment of glioblastoma (GBM). It can trigger...

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 tamoxifen-resistant breast cancer xenogr...

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 xe...

Approximately eighty percent of breast cancers are estrogen receptor alpha (ER-) positive, and although women typically initially respond well to anti-hormonal therapies such as tamoxifen and aromatase inhibitors, resistance often emerges. Fulvestrant is a steroid-based, selective estrogen receptor degrader (SERD) that both antagonizes and degrade...

Breast cancer is the most frequently diagnosed cancer among women and remains the second leading cause of cancer death in women. An estimated 70% of all breast cancers express estrogen receptor alpha (ERα); and endocrine therapies have validated ERα as a target for the treatment of breast cancer. Despite effective endocrine therapies, many patients...

Leukemia cells rely on two nucleotide biosynthetic pathways, de novo and salvage, to produce dNTPs for DNA replication. Here, using metabolomic, proteomic, and phosphoproteomic approaches, we show that inhibition of the replication stress sensing kinase ataxia telangiectasia and Rad3-related protein (ATR) reduces the output of both de novo and salv...

GDC-0810 and fulvestrant mouse pharmacokinetic data. (A) GDC-0810 mouse pharmacokinetics (B) Fulvestrant plasma concentrations. DOI: http://dx.doi.org/10.7554/eLife.15828.021

Primer sequences. (A) Transcriptional Real-time PCR Oligonucleotide Sequence (B) ER-ChIP Real-time PCR Oligonucleotide Sequence. DOI: http://dx.doi.org/10.7554/eLife.15828.022

Supplementary data tables related to the specificity for GDC-0810 in binding and activation of ER relative to other nuclear hormone receptors. (A) Radioligand binding assay (B) GDC-0810 nuclear hormone receptor reporter activity; agonist mode (C) GDC-0810 nuclear hormone receptor reporter activity; antagonist mode. DOI: http://dx.doi.org/10.7554/eL...

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 indu...

The majority of breast cancers express estrogen receptor alpha (ERα) and thus are treated with anti-hormonal therapies that directly block ER function (e.g.Tamoxifen) or hormone synthesis (Aromatase Inhibitors). While these therapies are initially effective, acquired resistance emerges and disease progression ensues. Importantly, the majority of th...

Background: Modulation of estrogen activity and/or synthesis is the mainstay therapeutic strategy in the treatment of estrogen receptor (ER)+ breast cancer (BC). However, many patients (pts) relapse or develop resistance to available hormonal agents via estrogen-dependent and estrogen-independent mechanisms. Furthermore, mutations in ESR1 affecting...

Background: Evidence that ER can signal in both ligand-dependent and independent manner in endocrine resistant breast cancer (BC) provides rationale for therapies that are not only functional antagonists of ER but also reduce ER levels, thus targeting both modes of signaling. Furthermore, mutations in ESR1 affecting the ligand-binding domain (LBD)...

Approximately eighty percent of breast cancers are estrogen receptor alpha (ER-) positive, and although women typically initially respond well to anti-hormonal 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 efficacy of nebulized sodium nitrite (AIR001) has been demonstrated in animal models of pulmonary arterial hypertension (PAH), but it was not known if inhaled nitrite would be well tolerated in human subjects at exposure levels associated with efficacy in these models. Inhaled nebulized sodium nitrite was assessed in three independent studies i...

Greater than 50% of high grade serous ovarian cancers express the estrogen receptor alpha (ERα). This observation, in addition to multiple lines of epidemiological and preclinical data, suggests that, similar to breast and endometrial cancer, estrogen receptor signaling may play a role in the development and progression of ovarian cancer. Unfortuna...

Historically, nitrogen oxides (NOx) in food, drinking water, as well as in the atmosphere have been believed to be associated with adverse health consequences. More recently, NOx have been implicated in normal homeostatic regulation, and exogenous administration has been associated with health benefits. One such potential health benefit is the pros...

Background: Modulation of estrogen synthesis or its receptor activity represents the treatment of choice for postmenopausal women with estrogen receptor-positive (ER+) breast cancer (BC). However, despite initial response to hormonal manipulation, most tumors ultimately develop endocrine resistance. The emerging evidence that ERα can signal in both...

ARN-509 is a novel androgen receptor (AR) antagonist for the treatment of castration-resistant prostate cancer (CRPC). ARN-509 inhibits AR nuclear translocation and AR binding to androgen response elements and, unlike bicalutamide, does not exhibit agonist properties in the context of AR overexpression. This first-in-human phase I study assessed sa...

The androgen receptor (AR) plays a central role in the development and progression of prostate cancer. Recent studies demonstrate that AR remains essential in the majority of castration resistant prostate cancer (CRPC) after classical androgen ablation therapies have failed. The clinical efficacies of MDV3100 and abiraterone acetate, both of which...

While endocrine therapies are initially effective to treat estrogen receptor (ERα) positive breast cancer tumors, acquired resistance invariably emerges. Although resistant tumors typically display changes in PI3K or other kinase pathways, the majority of these tumors continue to express and depend on ERα for growth and survival. Exploring the hypo...

Eighty percent of all breast cancers express the estrogen receptor alpha (ERα) and thus are treated with antihormonal therapies that directly block ERα function (e.g., tamoxifen) or hormone synthesis (aromatase inhibitors). While these therapies are initially effective, acquired resistance invariably emerges and disease progression ensues. Importan...

80% of all breast cancers express the estrogen receptor alpha (ERα) and thus are treated with anti-hormonal therapies that directly block ER function (e.g. Tamoxifen) or hormone synthesis (Aromatase Inhibitors). While these therapies are initially effective, acquired resistance invariably emerges. Importantly, the majority of these tumors continue...

TPS4697 Background: ARN-509 is a novel small molecule androgen signaling inhibitor that impairs AR nuclear translocation and binding to DNA, inhibiting tumor growth and promoting apoptosis, with no partial agonist activity. Preclinical data suggests that the maximal therapeutic index of ARN-509 can be achieved at low steady state plasma levels with...

4548 Background: ARN-509 is a novel small molecule AR antagonist that impairs AR nuclear translocation and binding to DNA, inhibiting tumor growth and promoting apoptosis, with no partial agonist activity. (Clegg et al., 2012) We conducted a phase I trial to assess safety, pharmacokinetics (PK), and determine the recommended phase II dose (RP2D). M...

Continued reliance on the androgen receptor (AR) is now understood as a core mechanism in castration-resistant prostate cancer (CRPC), the most advanced form of this disease. While established and novel AR pathway-targeting agents display clinical efficacy in metastatic CRPC, dose-limiting side effects remain problematic for all current agents. In...

The overproduction of nitric oxide during the biological response to inflammation by the nitric oxide synthase (NOS) enzymes have been implicated in the pathology of many diseases. By removal of the amide core from uHTS-derived quinolone 4, a new series highly potent heteroaromatic-aminomethyl quinolone iNOS inhibitors 8 were identified. SAR studie...

60–75% of all breast cancers express the estrogen receptor (ER) and thus are treated with anti-hormonal therapies that directly block ER function (e.g. Tamoxifen) or hormone synthesis (Aromatase Inhibitors). While these therapies are initially effective, acquired resistance invariably emerges. Importantly, the majority of these tumors continue to e...

28 Background: ARN-509 is a second-generation anti-androgen discovered in a screen to identify full androgen receptor (AR) antagonists in the context of AR over-expressing prostate cancer cells, a model for castration resistant prostate cancer (CRPC). It has been reported that other second-generation anti-androgens, MDV3100 and BMS-641988, can indu...

Optimization of a screening hit from uHTS led to the discovery of TGR5 agonist 32, which was shown to have activity in a rodent model for diabetes.

Three isoforms of nitric oxide synthase (NOS), dimeric enzymes that catalyze the formation of nitric oxide (NO) from arginine, have been identified. Inappropriate or excessive NO produced by iNOS and/or nNOS is associated with inflammatory and neuropathic pain. Previously, we described the identification of a series of amide-quinolinone iNOS dimeri...

Nitric oxide (NO) derived from neuronal nitric-oxide synthase (nNOS) and inducible nitric-oxide synthase (iNOS) plays a key role in various pain and inflammatory states. KLYP961 (4-((2-cyclobutyl-1H-imidazo[4,5-b]pyrazin-1-yl)methyl)-7,8-difluoroquinolin-2(1H)-one) inhibits the dimerization, and hence the enzymatic activity of human, primate, and m...

There are three isoforms of dimeric nitric oxide synthases (NOS) that convert arginine to citrulline and nitric oxide. Inducible NOS is implicated in numerous inflammatory diseases and, more recently, in neuropathic pain states. The majority of existing NOS inhibitors are either based on the structure of arginine or are substrate competitive. We de...

Selective androgen receptor modulators (SARMs) are a new class of molecules in development to treat a variety of diseases. SARMs maintain the beneficial effects of androgens, including increased muscle mass and bone density, while having reduced activity on unwanted side effects. The mechanisms responsible for the tissue-selective activity of SARMs...

The androgen receptor is a ligand inducible transcription factor that is involved in a broad range of physiological functions. Here we describe the discovery of a new class of orally available selective androgen receptor modulators. The lead compound, 6-[(2R,5R)-2-methyl-5-((R)-2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-1-yl]-4-trifluoromethylquinol...

Bimatoprost (Lumigan) is a pharmacologically unique and highly efficacious ocular hypotensive agent. It appears to mimic the activity of a newly discovered family of fatty acid amides, termed prostamides. One biosynthetic route to the prostamides involves anandamide as the precursor. Bimatoprost pharmacology has been extensively characterized by bi...

The objective of this study was to assess the corneal and scleral permeabilities of natural prostaglandins as well as their prodrugs and analogs through human cornea and sclera in vitro. The "apparent permeability coefficients" (Papp) of natural prostaglandins (PGF2alpha, PGD2 and PGE2), ester prodrugs of PGF2alpha (1-isopropyl PGF2alpha, 11-pivalo...

Tazarotene is a novel acetylenic retinoid for the treatment of psoriasis and acne. We examined (1) the hydrolysis of tazarotene in blood from Japanese-American and Caucasian subjects, (2) the esterases responsible for this hydrolysis in human blood, and (3) tazarotene hydrolysis in rat and human liver microsomes. Tazarotene hydrolysis and enzyme in...

The suitability of a dynamic lung slice culture system as an in vitro model for studying pulmonary metabolism of PGF2α was assessed. [3H]Prostaglandin F2α ([3H]PGF2α), a twenty carbon fatty acid that contains a five-carbon ring and is known to be metabolized by lung in vivo, was incubated with precision-cut rat lung slices in 1.7 ml of Waymouth's b...

This study was designed to examine the effect of benzalkonium chloride/ethylenediaminetetraacetic acid (BAK/EDTA) on the ocular bioavailability (Focular) of ketorolac tromethamine after ocular instillation to normal and de-epithelialized corneas of rabbits both in vitro and in vivo. The in vitro Focular of the formulations was measured in flow-thro...

Reduction of metabolic clearance is often a focus of chemistry efforts in lead optimization (Lead Op). As metabolic liabilities can only be addressed through new chemistry, they are best understood early in the optimization process. The goal of this work was to develop and validate a medium throughput in vitro assay, capable of ranking compounds wi...