“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 [...]

The Janssen gut-restricted COX-2 inhibitor, compound 10 , is a tool compound used to test the hypothesis that gut-restricted COX-2 inhibition would be beneficial for cancer without the cardiovascular risk of systemic COX-2 inhibition. Unfortunately, IVIVC of several compounds demonstrated that in vivo efficacy was not driven by gut COX-2 [...]

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 [...]

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.

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.