Emraclidine (CVL-231) is a selective positive allosteric modulator (PAM) of the cholinergic M4 muscarinic receptor and is the only selective M4 PAM in clinical development. The molecule has shown promising early results in schizophrenia with several Ph. II trials enrolling and is intended to be developed for Alzheimer’s Disease psychosis as [...]

YCT529 ( YourChoice ) is a potential non-hormonal male contraceptive with impressive preclinical oral efficacy that is expected to enter clinical development in the first half of 2023. This retinoic acid receptor alpha (RAR-α) antagonist, discovered by Gunda Georg ’s lab at the University of Minnesota, was first disclosed in 2022 and [...]

IL-17 has been a hot target in immunology thanks to the clinical and commercial success of marketed anti-IL-17A and anti-IL-17RA antibody drugs secukinumab (Cosentyx), ixekizumab (Talz), and brodalumab (Siliq) in psoriasis, psoriatic arthritis, and ankylosing sponylitis. With the recent identification of small molecule binders of IL-17A [...]

Ziftomenib (KO-539) is an oral menin-MLL1 protein-protein interaction inhibitor being developed for acute myeloid leukemia (AML) by Kura Oncology. This Sep. ’22 Molecule of the Month inhibits the protein–protein interaction between menin and mixed lineage leukemia (MLL) fusion proteins, an interaction that drives many leukemias. Early data [...]

Mavacamten is a first-in-class oral, selective, allosteric cardiac myosin inhibitor, discovered by Myokardia and acquired by BMS in 2020 in a whopping $13.1B transaction. In 2022 , it was approved by the FDA to treat obstructive hypertrophic cardiomyopathy (HCM) in adults and, thanks to its use, led to improvements in functional capacity and [...]

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 [...]

Resmetirom is an oral, liver-targeting, once-daily THRβ-selective agonist, which in December 2022 became the first drug to meet its primary endpoints in Ph. III for NASH, demonstrating both NASH resolution and no worsening of fibrosis by biopsy over placebo in 316 test patients. Madrigal will file an NDA for resmetirom in 2023, allowing it to [...]

Deucravacitinib (Sotyktu) is a first-in-class oral, allosteric tyrosine kinase 2 (TYK2) inhibitor, FDA-approved in September 2022 for moderate-to-severe plaque psoriasis. It is the first novel oral therapy for this indication in nearly 10 years, and is believed to potentially become the new standard of care. Deucravacitinib is the first de [...]

MRTX1133 is a non-covalent, reversible, long-acting inhibitor of KRAS G12D entering clinical development for cancer as an oral agent . Mutant KRAS proteins are well-known drivers of cancer, and only in recent years have the first KRAS inhibitors been approved. These inhibitors are covalent and only work on the KRAS G12C mutation, as they bind [...]

While the Molecules of the Month are being selected and our deep dive reviews are being prepared, you can find early highlights from our team’s journal club from February 2023. Check out AstraZeneca’s preclinical SERD, Merck’s Ph. I c-KIT inhibitor, University of Michigan’s STAT5 PROTAC degrader, and more snippets to jumpstart your reading [...]

In this update of small molecules in the news for February 2023, we will cover recent: - Molecules in Motion : clinical trial updates and FDA filings - Negative Readouts : halted, discontinued or altered clinical trials - Million-Dollar Molecules : recent M&A’s, IPOs, and other fundraising - Potential Approvals : recent NDA filings and [...]

Our Drug Hunter subscribers at Curie.Bio recently made headlines with the launch of their new >$500M venture fund with a new model for early-stage biotech financing to help founders launch therapeutics companies. Curie.Bio intends to act not only as an investor, but also as a day-to-day operating partner to help founders choose targets [...]

A Ph. IIb TYK2 inhibitor from Nimbus (just bought by Takeda) that may be more efficacious than deucravacitinib, the first and only approved CGRP receptor antagonist nasal spray for the treatment of acute migraines from BMS/Pfizer, a pomalidomide-derived Ph. I/Ib oral, IKZF2-selective molecular glue degrader for the treatment of advanced solid tumors from Novartis are just some of the examples for this month's MOTM.  Learn more about the molecules by navigating to the full reviews on the right (when released) which cover: why the molecules matter, how they were discovered, the key steps behind...

The first approved non-covalent BTK inhibitor. As the nexus of the B cell receptor (BCR) signaling pathway , BTK has been a hotly pursued target in B-cell-mediated cancers and immunological diseases , as evidenced by the many BTK inhibitors we’ve highlighted in just the past few years. Recently, pirtobrutinib (Jaypirca, LOXO-305) received [...]

What is it? Elacestrant ( Orserdu ) is an oral, selective estrogen receptor modulator and degrader (SERM/SERD) that was recently approved for ER-positive, HER2-negative, estrogen receptor ɑ (ESR1)-mutated advanced or metastatic breast cancer (345 mg PO QD) based on progression-free survival (PFS) data from EMERALD ( NCT03778931 ). As the [...]

What is it? Baxdrostat ( RO6836191 , CIN-107) is an oral aldosterone synthase (CYP11B2) inhibitor in several Ph. II trials (0.5-2 mg QD) for hypertension, CKD, and primary aldosteronism. The molecule is highly selective ( >100x ) against a cortisol synthesis enzyme, CYP11B1, allowing it to avoid negative effects due to cortisol reduction in [...]

PF-6870961 is a growth hormone secretagogue receptor 1a (GHSR1a) inverse agonist biased for inhibition of 𝜷-arrestin signaling, in contrast to its parent compound, PF-5190457, an unbiased GHSR1a inverse agonist. PF-6870961 was discovered as a major metabolite of [...]

A protein-protein interaction inhibitor for a challenging-to-drug master transcription factor. OICR12694 is an oral protein-protein interaction inhibitor targeting the challenging-to-drug oncogenic transcription factor, B cell lymphoma 6 (BCL-6) . As a master regulator of B cell differentiation in germinal centers and hence a common driver of [...]