compound 1 is a CD33 pre-mRNA splicing modulator that increases CD33 exon 2 skipping in cells. CD33/Siglec 3 regulates microglia activity, and genetic alterations of CD33 are associated with protection from Alzheimer’s. Alternative splicing of CD33 with exclusion of exon 2 is hypothesized to copy the protective effect of the human genetic [...]

GSK3640254 is an HIV maturation inhibitor and Ph. IIb clinical candidate (60-180 mg PO QD) with activity against a range of HIV strains with Gag polymorphisms. The first HIV maturation inhibitor to read out clinically was bevirimat (Myriad Genetics), derived from a natural product first isolated from a Chinese herb. Maturation inhibitors like [...]

MIW815 (ADU-S100) is a first-in-class STING agonist for cancer immunotherapy. Agonism of the STING (stimulator of IFN genes) receptor, true to its name, leads to stimulation of type I IFN production , aiding the antitumor immune response. Systemic activation of STING, however, may lead to negative immunologic effects such as cytokine storm [...]

DS-3801b is a non-macrolide GPR38 agonist and a Ph. I clinical candidate for treatment of chronic constipation (SAD 1-100 mg PO). GPR38 is the receptor for the GI hormone motilin, which as the name suggests, regulates GI motility. Agonism of GPR38 is expected to reduce constipation by activating GI tract smooth muscle cells to move things [...]

LEO 134310 is a non-steroidal, selective glucocorticoid receptor (GR) agonist in Ph. I for plaque psoriasis. Glucocorticoid receptor modulators are widely used in tissue-restricted forms (think Flonase) for their acute effects, but prolonged engagement of GR is undesirable. Previously LEO Pharma described the identification of this topical [...]

bradanicline (ATA-101 or TC-5619) is a molecule first disclosed a decade ago by Targacept. It is a selective agonist of the alpha-7 neuronal nicotinic acetylcholine receptor, and was intended as a drug candidate for treatment of cognitive impairment in neurological disorders. It is highly selective for the CNS over peripheral receptor [...]

There were four novel drugs approved by the FDA in January 2022 (2 small molecules, 2 large molecules). The novel January 2022 new drug approvals appear below in this Drug Hunter minireview: See our overview of all 36 of the novel small molecule and large molecule FDA [...]

Pfizer’s PF-07321332 (API of Paxlovid) is an oral, reversible covalent SARS-CoV-2 main protease inhibitor, which received emergency use authorization from the FDA for Covid treatment at the end of 2021. Clinical data showed Paxlovid reducing Covid hospitalization and death by 89%. It was nominated for November’s cover by Mike Koehler [...]

MK-0616 is a macrocyclic PCSK9 inhibitor with demonstrated once-daily PCSK9-lowering and LDL-cholesterol-lowering activities in a human clinical trial (<300 mg QD). Currently PCSK9-targeting therapies are only available by injection, and the cost-benefit of using large molecules to lower cholesterol has been hotly debated. Identification of [...]

The ARIAD/Takeda EGFR exon 20 insertion mutant (EGFRex20ins) inhibitor TAK-788 is a Breakthrough Therapy for patients with advanced non-small cell lung cancer (NSCLC) whose tumors harbor EGFR exon 20 insertion mutations.  The appearance of exon 20 insertions is a common resistance mechanism to earlier generations of EGFR inhibitors including [...]

The Lilly glucagon-like peptide-1 receptor (GLP-1R) agonist ( LSN3318839 ) is a positive allosteric modulator intended to treat type 2 diabetes. This drug candidate has an interesting proposed mechanism as a molecular glue between GLP-1R and GLP peptide, enhancing endogenous peptide activity. GLP-1 agonism is a well-established mechanism for [...]

The Genentech PI3Kα isoform-selective kinase inhibitor and mutant PI3Kα degrader inavolisib selectively depletes the oncogenic mutant p110α catalytic subunit of PI3Kα in cancer cells with active receptor tyrosine kinase (RTK) signaling. The gene encoding p110α, PIK3CA, is one of the most frequently mutated oncogenes, with over 2M cancer [...]

MRTX1133 was nominated as December 2021’s cover molecule by reviewers Joachim Rudolph and Julien Lefranc . MRTX1133 is a non-covalent inhibitor of KRASG12D that demonstrated tumor regression in a mouse xenograft model when dosed IP (maximum efficacy at 10-30 mg/kg, activity as low as 3 mg/kg). Joachim said, “The discovery of MRTX1133 deserves [...]

The Arvinas ER chimeric degrader, ARV-471 , is an oral, bioavailable ER degrading CRBN-based  PROTAC for the treatment of patients with ER+/HER2- breast cancer. Along with ARV-110 , it is one of the first chimeric degraders to enter a Ph. II clinical trial. It was first disclosed at AACR in early 2021, and though the molecules have not been [...]

The Kronos CDK9 inhibitor, KB-0742, is an ultraselective inhibitor of cyclin-dependent kinase CDK9. The CDK family of kinases have been pursued as cancer drug targets for decades, but family selectivity within the highly conserved kinase family has made it difficult to identify highly selective molecules, resulting in less than ideal [...]

The Revolution Medicines KRASG12C inhibitor, RM-018, “glues” KRASG12C to the highly abundant chaperone protein, cyclophilin A, in a tri-complex (KRAS- inhibitor-cyclophilin A) stabilized by protein-protein interactions. An undisclosed molecule in their pipeline with a related mechanism, RMC-6291 , has been reported to be orally bioavailable [...]

The H3 Biomedicine RNA splicing modulator, H3B-8800 , targets the spliceosome SF3b complex containing either wild-type (WT) or mutant SF3B1. Splicesome inhibition can induce synthetic lethality since cancer cells bearing spliceosome mutations are more dependent on WT spliceosome function. The compound is derived from the natural product [...]

The Biocryst oral plasma kallikrein inhibitor, berotralstat (BCX7353) , was recently approved as the first non-steroidal treatment for prevention of hereditary angioedema attacks. The molecule is given orally (150 mg QD) despite having two basic amines. Interestingly for a chronically administered drug, the molecule is noted to have QT [...]