Zilucoplan is a macrocyclic peptide-containing drug with 15 amino acids in total, targeting the challenging-to-drug C5 complement protein and formulated for self-administered once-daily SC injection. In Sept. 2023, zilucoplan received its first global approval in Japan, followed in Oct. 2023 by FDA approval for gMG patients who are AChR antibody-positive, making zilucoplan the first drug derived from mRNA display for cyclic peptides to be approved. This case study discusses how zilucoplan was discovered and why it’s an important scientific milestone for the industry.

Inaxaplin (VX-147), developed by Vertex, is an inhibitor of APOL1 channel activity currently in a Ph. II/III pivotal study for the treatment of chronic kidney disease caused by specific variants of the APOL1 gene. It was recently granted Breakthrough Therapy designation by the FDA and PRIME designation by the EMA. The discovery story, which is an excellent case study for the use of MetID. Inaxaplin has been called “the most important genomic-driven drug discovery for chronic kidney disease this century”, acting on a target with a fascinating human genetic validation story.

Leniolisib is a selective PI3Kδ inhibitor that received approval in March 2023 from the FDA as a first-in-class treatment for activated PI3K-δ syndrome (APDS), a genetic immunodeficiency disorder caused by PI3Kδ activation. The leniolisib discovery program is notable for several reasons: it is a first approval for a PI3K inhibitor outside of oncology; the first approved drug for APDS; has a novel chemotype that appears to avoid safety issues that led to black box warnings seen with other PI3K molecules; and it overcame a polymorph issue with an early lead that led to inconsistent exposures.

JNT-517 is Jnana Therapeutics' first-in-class cryptic allosteric SLC6A19 inhibitor to treat phenylketonuria (PKU). This is a notable case study employing a novel lead generation approach with photoaffinity probes, leading to a clinical candidate for a historically challenging-to-drug target class. Read the case study to learn how Jnana used their RAPID technology to quickly generate allosteric inhibitor hits, the SAR that led to the discovery of JNT-517, and why the molecule is notable.

Last year, Biogen announced that it would acquire Texas biotech Reata Pharmaceuticals for $7.3B. Reata’s lead molecule, omaveloxolone (SKYCLARYS®), an oral, reversible covalent inhibitor of the E3 ligase KEAP1, became the first drug approved for Friedrich’s Ataxia. Omaveloxolone was previously highlighted as a Molecule of the Month in July 2023. Now, this 2023 Molecule of the Year nominee reflects a historic milestone for neurological drug discovery. This comprehensive explainer dives into Nrf2 target rationale, how it works, how the drug was discovered, its synthesis, and why it’s a big deal.

This article highlights million-dollar molecules that were recently in the news with related patent applications that give clues to their structures and properties. This edition includes Maze’s glycogen synthase 1 (GYS1) inhibitors that were recently licensed to Sanofi, allosteric androgen receptor (AR) modulators that may be of interest to targeted protein degradation researchers, brain-penetrant HER2 and ROCK2 inhibitors, and MDM2 degraders.

Induction of fetal hemoglobin expression by a PRC-targeting small molecule. Pociredir (FTX-6058) is an oral, allosteric polycomb repressive complex 2 (PRC2) inhibitor that binds embryonic ectoderm development protein (EED) within this complex, ultimately boosting fetal hemoglobin (HbF) expression . Increasing HbF levels has been shown to [...]

In 2022, Amgen acquired ChemoCentryx for $4B in cash, primarily for avacopan, a first-in-class treatment approved in 2021 for a rare automimmune condition, anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Scientifically, it is notable that avacopan is the first small molecule targeting the complement pathway to be [...]

Voxelotor is a first-in-class, reversible covalent aldehyde drug that prevents the hemoglobin polymerization, a primary driver of sickle cell disease. Approved in 2019 , this molecule represented a scientific milestone as a modern example of a reversible covalent drug being approved in a chronic indication. It is the first oral drug that [...]

Toward an oral, once-daily non-peptide STT2 agonist. Paltusotine a novel oral somatostatin receptor 2 (SST2) agonist and Crinetics’ lead investigational drug, is intended to treat acromegaly and neuroendocrine tumors (NETs) in carcinoid syndrome. Both diseases have been treated with surgery and injectable somatostatin [...]

Billion-Dollar Molecules: Etavopivat, an Allosteric PKR Kinase Activator for Sickle Cell Disease Abstract. Novo Nordisk has acquired Forma Therapeutics for $1.1B for its primary investigational drug, etavopivat. Etavopivat, a past Molecule of the Month , is an oral, once-daily allosteric activator of pyruvate kinase-R (PKR), which is [...]

An oral, brain-penetrant splicing modulator targeting ELP1. Incorrect splicing of the Elongator complex protein 1 (ELP1) gene causes Familial Dysautonomia (FD), a neurodegenerative disease that results in uncoordinated movement, blindness through retinal degeneration, and risk of unexplained sudden death, among other symptoms. A single T-to-C [...]

Abstract. Voxelotor, a gram-daily reversible covalent aldehyde drug, is an approved first-in-class oral drug that prevents the hemoglobin polymerization that drives sickle cell disease. It was one of several agents in clinical trials acquired from Global Blood Therapeutics by Pfizer as part of an over $5 billion buyout. In this article, we [...]

Amgen has acquired ChemoCentryx in a deal that includes lead molecule avacopan (Tavneos), a first-in-class orally bioavailable small molecule complement 5a receptor (C5aR) antagonist approved as an adjunctive treatment to standard of care therapy for adults with severe active anti-neutrophil cytoplasmic autoantibody (ANCA)-associated [...]

In June 2022, the FDA approved vutrisiran (Amvuttra), a small interfering RNA (siRNA) for polyneuropathy of hereditary transthyretin-mediated (ATTR) amyloidosis in adults. This deep dive explores the drug in more detail, including the industry context, the clinical data, the target rationale, the mechanism of action, and the drug’s origins [...]

A first-in-class intravenous kappa opioid receptor (KOR) agonist, an oral soluble guanylate cyclase (sGC) stimulator, a first-in-class subcutaneous complement C3 inhibitor, and an oral contraceptive comprising a synthetic progesterone (drospirenone) and a plant-based estrogen (estetrol) make up the final group of novel drugs from 2021 that we [...]

The FDA approved five new drugs in 2021 for use for genetic conditions, including molybdenum cofactor deficiency, Von Hippel-Lindau (VHL) disease, achondroplasia, and progressive familial intrahepatic cholestasis (PFIC). This article and slide deck reviews each in detail, including their mechanisms of action, originators, key clinical data [...]

Context. Etavopivat (Forma Therapeutics) is an oral erythrocyte pyruvate kinase activator being developed for sickle cell disease and other hemoglobinopathies , previously reported in 2019 . Hydroxyurea had been the only approved drug for sickle cell disease until the “sickle cell drug boon” began in 2017 starting with approval of l-glutamine [...]

This article reviews the novel drugs approved by the FDA in February 2022. together with Dr. Naveed Yasin, Dr. Vinicius Texeira, and Dr. Jennifer Huen Three novel molecules were approved in February 2022: Small molecules: Pyrukynd (mitapivat) : An oral pyruvate kinase activator approved for the treatment of hemolytic anemia in adults with [...]

The FDA recently approved Agios' Pyrukynd (mitapivat, AG-348) , a first-in-class, allosteric activator of pyruvate kinase (PK), for treatment of hemolytic anemia in adults with the genetic condition, pyruvate kinase deficiency. The drug is given orally with a starting dose of 5 mg BID, titrating up to 50 mg BID depending on hemoglobin (Hb) [...]

Mutated Huntingtin (HTT) protein is the cause of Huntington’s disease (HD). HTT-D3 is an oral, CNS-penetrant molecule with human HTT lowering activity in vivo used to illustrate the science around PTC Therapeutics’ Huntingtin’s disease program. PTC had filed patent applications for the HD program as early as November 2016 ( WO201700726 ). PTC [...]

The Pfizer CFTR potentiator, CP-628006 , enhances CFTR function in cystic fibrosis patient-derived airwell cells with a distinct mechanism of action from existing potentiators such as ivacaftor. It has a unique chemical structure, and in contrast to other potentiators does not seem to inhibit the channel at high concentrations of drug and [...]

The Mirum Pharmaceuticals IBAT bile acid transporter inhibitor, maralixibat , has a long history, having been first patented by scientists at Searle in 1994 and published by the time Searle became part of Pharmacia in 2005 . It was finally approved in Sep. 2021 for treatment of cholestatic pruritis in patients with Alagille Syndrome, and is [...]

The Takeda cholesterol 24-hydroxylase inhibitor, soticlestat (TAK-935, previously OV935) is a potent, highly selective, first-in-class inhibitor of the brain-specific enzyme cholesterol 24-hydroxylase (CH24H). Cholesterol 24-hydroxylase converts cholesterol to 24S-hydroxycholesterol, which acts as a positive allosteric modulator of [...]

The Galapagos CFTR potentiator, GLPG2451, is an oral, once-daily clinical candidate for cystic fibrosis (5-80 mg QD). It was advanced into a high-profile Ph. II triple-combo study with the CFTR correctors GLPG2737 and GLPG2222 in partnership with AbbVie, and was seen as a potential competitor to Vertex’s CF franchise, but unfortunately weak [...]

“compound 18” is an oral inducer of fetal hemoglobin (HbF) intended to treat anemias such as sickle cell disease and beta-thalassemia. The authors identified a weak hit (>10 uM) from a high-throughput phenotypic screen using human umbilical cord blood-derived erythroid progenitor cells. Optimization led to the azaspiro[3.3]heptane-containing [...]

“Compound 19” is a selective brain-penetrant inhibitor of the ceramide galactosyltransferase UGT8, intended for use in substrate reduction therapy for rare lysosomal storage disorders. The compound has good oral exposure in higher species (%F = 52 in dog) and is active in models looking at enzymatic activity using isotopically-labeled [...]

On Feb. 16, 12:00PM PST, Dr. Mira Pochon, Staff Scientist and Head of Translational Biology at Global Blood Therapeutics, gave a PBSS/CLSA webinar on one of 2019's drug approvals , voxelotor (GBT440).  Mira has been with GBT since it’s early days in 2011.  GBT’s chemistry team was led by their CSO Dr. Brian Metcalf, former head of drug [...]