introduction to molecules
of the month
This series highlights small molecules with recently published data or stories
that are relevant and inspirational to our work. Scroll down to learn more.
October’s molecule, the Bayer hGnRH-R antagonist BAY 1214784, is intended as an oral, once-daily treatment for uterine fibroids, a highly common problem in adult women that can lead to infertility. Existing treatments include hGnRH-R blockers which have undesirable side effects such as induction of menopausal symptoms due to their influence on both LH and FSH hormone levels. The chemically distinct Bayer molecule differentiates from prior molecules by having a PK/PD profile that allows only partial lowering of LH levels only. The bar for safety in a large indication with otherwise healthy individuals is very high, but BAY 1214784 successful advanced to clinical testing and completed a Ph. I study with good tolerability at doses up to 450 mg QD.
April 2020’s molecule, the Mirati KRAS G12C inhibitor MRTX849, has been a hotly followed compound in development as it is the closest clinical KRAS inhibitor to the likely soon-to-be approved AMG-510 (sotorasib). The KRAS clinical race easily would have been the most followed development story of 2020 had it not been for COVID, due to the significant disease burden of KRAS-mutant-driven tumors in large indications including lung cancer. That Mirati’s KRAS clinical data has led to a nearly $10B appreciation in its equity value prior to an approval says everything about expectations for KRAS inhibitors in cancer. The recent successes of covalent inhibitors in cancer for targets like BTK, FGFR, and KRAS G12C are driving a major resurgence in interest for covalent inhibitors in modern drug discovery.
GS-6207 is an HIV-1 inhibitor that acts on the capsid protein monomer (p24), which normally self-assembles in the HIV virion to form the capsid core that is essential for virus infectivity. GS-6207 targets a protein-protein interaction between the small (24 kDa) p24 monomers, binding in a glue-like fashion to two separate monomers, and is able to overcome the high concentration of p24 in a virion (~4 mM!) to inhibit HIV activity with sub-nanomolar potency in cells (20-500 pM). Since the HIV capsid protein is highly conserved among HIV-1 variants, GS-6207 shows high synergy and no cross-resistance with approved anti-HIV agents. GS-6207 was found to be generally safe and well-tolerated in Ph. I and showed evidence of antiviral activity. Amazingly, this small molecule has the half-life one might expect of a well-engineered biologic drug, and is being dosed subcutaneously once every 6 months in the Ph. II/III study. Definitely a candidate for “molecule of the year!”
The Molecules of the Month Process
Research publications from each month are reviewed
Nominations for selection are accepted from readers and reviewers
Candidates are finalized by the editorial team and sent for community review and comment
Molecules of the Month are published for public feedback
Corresponding authors are notified for comment or correction and final edits are made
what makes a great molecule
Reviewers and editors focus on:
- First disclosures of molecules or new properties
- Clinical candidates with interesting profiles
- Non-clinical molecules with intriguing modes of action
- Interesting structures or unique properties
- Drug discovery stories with educational value
- Nominations by readers and reviewers
Drug Discovery Resources
- Drug Discovery Resources
- Drug Discovery Posters and Cheat Sheets
- Drug Discovery IPOs and Industry Reviews
- Lists of Approved Drugs
- Classics in Drug Discovery
- Drug Discovery Books
- Drug Discovery Conferences
- What is a Drug Hunter?
- Topliss Tree and Topliss Scheme Posters
- PK Reference Table / Cheat Sheet
- Pd-Couplings Table / Cheat Sheet