Protein-degrading drugs and molecular glues account for one-third of the "Drug Hunters" annual list of small molecules

A few days ago, the drughunter website (drughunter.

Pfizer's new coronavirus Mpro protease inhibitor

Image source: Reference [1]

The new coronavirus Mpro protease inhibitor PF-07321332 developed by Pfizer is based on a candidate molecule against the SAR virus protease

Arvinas' Estrogen Receptor PROTAC Degrader

Image source: Reference [1]

ARV-471, an estrogen receptor (ER) PROTAC degrader developed by Arvinas, is an oral bispecific molecule

Kronos Bio's CDK9 inhibitor

Image source: Reference [1]

Kronos Bio's KB-0742 is a highly selective CDK9 inhibitor

Image source: Reference [2]

Using this technology, the company has discovered small-molecule compounds that bind to the androgen receptor alternative splice variant (AR-V)

Merck's oral PCSK9 inhibitor

▲ Compound 44 (Image source: Reference [3])

The oral PCSK9 inhibitor developed by Merck & Co.

Mirat's KRAS G12D inhibitor

Image source: Reference [1]

MRTX1133, developed by Mirati, is a non-covalent reversible KRAS G12D inhibitor that binds to KRAS G12D mutants in both inactive and activated states, and shows high specificity for KRAS G12D mutants.

Takeda's EGFR Exon 20 Insertion Mutation Inhibitor

Image source: Reference [1]

Takeda's oral tyrosine kinase inhibitor mobocertinib is an oral therapy specifically designed to target EGFR exon 20 insertion mutations

In September last year, it was approved by the U.

Eli Lilly's molecular glue targeting GLP-1R

Image source: Reference [1]

LSN3318839, developed by Eli Lilly, is a positive allosteric modulator targeting the glucagon-like peptide-1 receptor (GLP-1R)

Revolution Medicines' KRAS G12C inhibitor

Image source: Reference [1]

RM-018, developed by Revolution Medicines, is a small molecule inhibitor that inhibits the activity of KRAS G12C mutants by binding to their activated state

Because this mechanism of action is very different from covalent inhibitors (such as Lumakras and adagrasib) that usually bind to the inactive state of KRAS G12C

Genentech's PI3Kα mutant degraders

Image source: Reference [1]

Roche's Genentech company developed inavolisib (GDC-0077), a selective inhibitor of PI3Kα mutants

▲Inavolisib (GDC-0077) can specifically degrade PI3Kα mutants (Image source: Genentech official website)

Oral RNA splicing modulators from H3 Biomedicine

Image source: Reference [1]

RNA splicing is critical to cellular function, and cells use a complex called the spliceosome that catalyzes the excision of introns from RNA precursors and joins exons together to generate mature RNA

Biocryst's Oral Kallikrein Inhibitors

Image source: Reference [1]

Orladeyo (berotralstat), an oral kallikrein inhibitor developed by Biocryst, received FDA approval in 2020 for the prevention of hereditary angioedema (HAE) episodes in adults and pediatric patients over 12 years of age

Genentech's estrogen receptor degraders

Image source: Reference [1]

Genentech's investigational therapy giredestrant (GDC-9545) is a potential "best-in-class" selective estrogen receptor degrader (SERD)

The results of a phase 2 clinical trial announced at last year's ESMO conference showed that giredestrant, as a neoadjuvant therapy, combined with the CD4/6 inhibitor palbociclib, combined biomarkers associated with tumor proliferation in patients with early-stage ER-positive, HER2-negative breast cancer The level of Ki67 decreased by 80%, which was significantly better than that of the active control group (67%, p=0.
0222)
.
Furthermore, 25% of tumors showed complete cell cycle arrest by the second week of treatment, compared with 5.
1% in the control group
.

It is currently being tested in a Phase 3 clinical trial in combination with palbociclib in patients with ER-positive, HER2-negative locally advanced or metastatic breast cancer
.

References:

[1] 2021 Small Molecules of the Year.
Retrieved February 15, 2022, from https://drughunter.
com/molecules-of-the-year/2021/

[2] Richters et al.
, (2021).
Modulating Androgen Receptor-Driven Transcription in Prostate Cancer with Selective CDK9 Inhibitors.
Cell Chemical Biology, https://doi.
org/10.
1016/j.
chembiol.
2020.
10.
001

[3] Tucker, et al.
, (2021).
A Series of Novel, Highly Potent, and Orally Bioavailable Next-Generation Tricyclic Peptide PCSK9 Inhibitors.
J.
Med.
Chem, https://doi.
org/10.
1021/acs.
jmedchem.
1c01599