Morphic Therapeutic’s MORF-627 is an oral αvβ6 integrin inhibitor designed to treat IPF by blocking the TGFβ pathway. The Morphic team leveraged SBDD and FEP+ during lead optimization to enhance permeability and isoform selectivity. This article highlights the team’s focus on inhibiting the “bent-closed” conformation of αvβ6 as well as the linker design that led to the “chameloenicity” of the lead compound. The impressive multispecies PK and in vivo efficacy of MORF-627 in preclinical models was unfortunately accompanied by oncogenic toxicity that prevented it from reaching clinical trials.

BAY 2925976 is a novel oral ARα2C antagonist developed by Bayer for the treatment of OSA (obstructive sleep apnea), a widespread condition affecting nearly one billion people globally. Despite the availability of mechanical treatments like CPAP, poor adherence rates highlight the need for more effective interventions. BAY 2925976 demonstrated a preclinical proof of concept for ARα₂C modulation as a potential therapeutic approach for OSA. In this article, we detail the discovery of BAY 2925976, as highlighted by Michael Hahn at the ACS Fall 2024 First-Time Disclosures session in Denver, CO.

Genentech’s GDC-6599 is the first oral TRP Ankyrin 1 (TRPA1) antagonist to reach Ph. IIa (NCT05660850) for chronic cough after preclinical studies and a Ph. I trial showed it was well-tolerated, in contrast to prior molecules. The transient receptor potential (TRP) family of ion channels has been the subject of intensive drug discovery efforts due to their critical role in the development and progression of pain, itch, and respiratory conditions.

RPT193, an oral, second-generation CCR4 inhibitor from RAPT Therapeutics, is in Ph. II clinical trials (400 mg QD) to treat atopic dermatitis (AD) (NCT05399368) and asthma (NCT05935332). CCR4 has been a long outstanding therapeutic target for treating inflammatory diseases, but despite many efforts, no molecule inhibiting this receptor has progressed beyond Ph. I for these indications.

Ziretaxestat, an oral autotaxin (ATX) inhibitor originated by Galapagos, once garnered excitement as the first molecule to complete a Ph. III clinical program in idiopathic pulmonary fibrosis since the approvals of nintedanib and pirfenidone. Following the disappointing clinical data and discontinuation of the molecule, this annotation revisits ziritaxestat in the context of other inhibitors, recaps the therapeutic hypothesis and how it was discovered, summarizes notable molecular properties for drug discovery scientists, and discusses what happened and what’s next.

Context. CHF-6366 (Chiesi Farmaceutici S.p.A) is a muscarinic antagonist and β2 agonist (MABA) being developed as an inhaled treatment for respiratory diseases. Muscarinic antagonists and β2 agonists both act to inhibit bronchoconstriction, but through different mechanisms, making the combination of both agents a desirable strategy for [...]

CC-90001 was nominated by reviewer Christian Kuttruff . CC-90001 is a JNK (c-Jun N-Terminal Kinase) inhibitor and a Phase II clinical candidate for idiopathic pulmonary fibrosis ( NCT03142191 ). Christian says, “Preclinical evidence suggests that c-Jun N-terminal kinase (JNK) enzyme function is required for key steps in the pulmonary fibrotic [...]

Velsecorat (AZD7594) is an inhaled, non-steroidal glucocorticoid receptor modulator and antedrug (soft drug) for treatment of asthma and other respiratory conditions that has completed several Ph. II studies . While the paper states that the results support progression into Ph. III studies, a Ph. III study does not appear to have started and [...]

This month’s cover molecule, BMS-986278 , is an LPA 1 antagonist and oral (up to 125 mg BID) Ph. II clinical candidate for idiopathic pulmonary fibrosis (IPF) (NCT04308681). Reviewer and nominator Christian Kuttruff says: “While there are two approved molecules for the treatment of IPF (pirfenidone from Roche and nintedanib from BI), there is [...]

The Shionogi P2X3 ligand-gated ion channel antagonist, sivopixant ( S-600918 ), is an oral Ph. II candidate for refractory chronic cough, which recently completed a its Ph. IIb study, overcoming the projected high dose requirement of a prior preclinical candidate. The molecule has a very polar core structure with both a dioxotriazine and [...]

The ImmunoMet OXPHOS modulator (PC1 inhibitor), IM156 , is a derivative of the long-used biguanide diabetes drug, metformin, that appears to have activity in lung fibrosis models. The therapeutic hypothesis for IPF is that myofibroblasts play an essential role in extracellular matrix remodeling and fibrogenesis that lead to loss of pulmonary [...]

OATD-01 (OncoArendi Therapeutics oral, first-in-class CHIT1/AMCase chitinase inhibitor clinical candidate)

X-165 is an autotaxin inhibitor clinical candidate for idiopathic pulmonary fibrosis discovered using a 3-cycle DEL screen of 225M compounds derived from amide couplings. An unusual spirocyclic amine building block was responsible for most of their non-phosphonate-containing high-enrichment hits. The initially resynthesized hits had [...]