LEO 134310

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 [...]

LEO 134310 is a non-steroidal, selective glucocorticoid receptor (GR) agonist in Ph. I for plaque psoriasis. Glucocorticoid recept...

bradanicline (ATA-101 or TC-5619)

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 [...]

bradanicline (ATA-101 or TC-5619) is a molecule first disclosed a decade ago by Targacept. It is a selective agonist of the alpha-...

Daridorexant, Abrocitinib, Tebentafusp, and Faricimab Among Drug Approvals in Jan. 2022

together with Dr. Naveed Yasin, Dr. Jen Huen, and Dr. Adrian Parodi 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 [...]

together with Dr. Naveed Yasin, Dr. Jen Huen, and Dr. Adrian Parodi There were four novel drugs approved by the FDA in January 202...

PF-07321332: an Oral, Reversible Covalent SARS-CoV-2 Main Protease Inhibitor

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 [...]

Pfizer’s PF-07321332 (API of Paxlovid) is an oral, reversible covalent SARS-CoV-2 main protease inhibitor, which received emergenc...

MK-0616: a Macrocyclic PCSK9 Inhibitor

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 [...]

MK-0616 is a macrocyclic PCSK9 inhibitor with demonstrated once-daily PCSK9-lowering and LDL-cholesterol-lowering activities in a ...

TAK-788: an EGFR Exon 20 Insertion Mutant (EGFRex20ins) Inhibitor for Patients with Advanced Non-Small Cell Lung Cancer (NSCLC)

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 ARIAD/Takeda EGFR exon 20 insertion mutant (EGFRex20ins) inhibitor TAK-788 is a Breakthrough Therapy for patients with advance...

LSN3318839: a GLP-1R GLP Glue with Positive Allosteric Modulation

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 Lilly glucagon-like peptide-1 receptor (GLP-1R) agonist ( LSN3318839 ) is a positive allosteric modulator intended to treat ty...

Inavolisib: an PI3Kα Isoform-Selective Kinase Inhibitor and Mutant PI3Kα Degrader

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 [...]

The Genentech PI3Kα isoform-selective kinase inhibitor and mutant PI3Kα degrader inavolisib selectively depletes the oncogenic mut...

MRTX1133: a Non-Covalent Inhibitor of KRASG12D

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 [...]

MRTX1133 was nominated as December 2021’s cover molecule by reviewers Joachim Rudolph and Julien Lefranc . MRTX1133 is a non-coval...

ARV-471: an Oral ER Degrader for ER+/HER2- Breast Cancer

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 Arvinas ER chimeric degrader, ARV-471 , is an oral, bioavailable ER degrading CRBN-based  PROTAC for the treatment of patients...

KB-0742: an Ultraselective Inhibitor of Cyclin-Dependent Kinase CDK9

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 Kronos CDK9 inhibitor, KB-0742, is an ultraselective inhibitor of cyclin-dependent kinase CDK9. The CDK family of kinases have...

RM-018: a KRASG12C-Cyclophilin A Glue

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 Revolution Medicines KRASG12C inhibitor, RM-018, “glues” KRASG12C to the highly abundant chaperone protein, cyclophilin A, in ...

H3B-8800: an H3 Biomedicine RNA Splicing Modulator

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 H3 Biomedicine RNA splicing modulator, H3B-8800 , targets the spliceosome SF3b complex containing either wild-type (WT) or mut...

Berotralstat (BCX7353): an Oral Plasma Kallikrein Inhibitor

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 [...]

The Biocryst oral plasma kallikrein inhibitor, berotralstat (BCX7353) , was recently approved as the first non-steroidal treatment...

Giredestrant (GDC-9545): an Oral Selective Estrogen Receptor Degrader and Full Antagonist

The Genentech next generation oral SERD (selective estrogen receptor degrader) and full antagonist, giredestrant (GDC-9545) , is a potential best-in-class Ph. III candidate for ER+, HER2- breast cancer (NCT04546009). It is the third SERD clinical candidate from Genentech (after GDC-0810 and GDC-0927) and a number of oral SERDs have previously [...]

The Genentech next generation oral SERD (selective estrogen receptor degrader) and full antagonist, giredestrant (GDC-9545) , is a...

2021 Large Molecule Drug Approvals Review – Pt. 2

This deep dive into 2021’s novel large molecule drug approvals is the 2 nd in a series of focus articles on 2021’s novel large molecule drugs. See part one here . For each of the 16 large molecule drug approvals of 2021 (excluding vaccines), we’ll [...]

This deep dive into 2021’s novel large molecule drug approvals is the 2 nd in a series of focus articles on 2021’s novel large mol...

Advisory Board: Andrew Setikas

Announcement: Appointment of Drug Hunter Advisory Board Member: Andrew Setikas Drug Hunter is pleased to introduce a new member of our Advisory Board, Andrew Setikas. As Chief Business Officer at California Life Sciences, Andrew Setikas has been at the forefront of record growth for the organization, and during his tenure spearheaded efforts [...]

Announcement: Appointment of Drug Hunter Advisory Board Member: Andrew Setikas Drug Hunter is pleased to introduce a new member of...

2021 Large Molecule Drug Approvals Review

This high-level overview of 2021’s novel large molecule drug approvals is the 2 nd in a series of focus articles on 2021’s new drugs (see the small molecules here ). You can find our deep-dive on 2021's large molecule drug approvals here . There were: [...]

This high-level overview of 2021’s novel large molecule drug approvals is the 2 nd in a series of focus articles on 2021’s new dru...