▎ WuXi AppTec content team editor
A few days ago, the Drug Hunter website (drughunter.com) released the annual list of small molecules, based on the nominations of readers and reviewers, 12 small molecules of the year were selected. The introduction to the Drug Hunter website notes that factors in the list of these small molecule compounds include clinical period and commercialization progress, technological innovation, and proof-of-concepts for new scientific principles. It is worth mentioning that 4 protein degraders and molecular gels are on the list, showing the industry's attention to these innovative treatment models.
Pfizer's new coronavirus Mpro protease inhibitor
Image source: References[1]
Arvinas estrogen receptor PROTAC degrader
Arvinas developed estrogen receptor (ER) PROTAC degrader ARV-471 is an oral bispecific molecule. It can recruit the E3 ligase CRBN near er, and label er ubiquitin, causing them to be degraded by the proteasome. In clinical trials for the treatment of locally advanced or metastatic ER-positive, HER2-negative breast cancer, the latest results showed that ARV-471 reduced ER levels by up to 90%, and in 34 patients who could assess clinical benefit (including confirmation of complete remission, partial remission, or disease stabilization for more than 24 weeks), the clinical benefit was 41%. Pfizer has entered into an R&D collaboration with Arvinas to jointly develop this PROTAC protein degradation therapy.
CDK9 inhibitor of Kronos Bio
Kronos Bio's KB-0742 is a highly selective CDK9 inhibitor. It comes from the company's small molecule microarray screening technology. This technique fixes different small molecules on a slide and then uses them to discover proteins or protein complexes that can bind to them. This technique could help discover small molecule compounds that bind to target protein complexes in physiologically relevant cell lysate environments.
Image source: References[2]
Using this technique, the company discovered small molecule compounds capable of binding to androgen receptor replacement splicing variants (AR-V). It is capable of modulating AR-mediated gene transcription. The oral CDK9 inhibitor KB-0742 was further optimized. It can reduce the expression of the oncogene MYC by inhibiting the activity of CDK9. It is currently used in Phase 1/2 clinical trials to treat patients with solid tumors carrying MYC amplification. Preliminary results published in November last year showed that KB-0742 had a long plasma half-life and exhibited dose-dependent target inhibitory activity.
Oral PCSK9 inhibitors of merck
Compound 44 (Image source: References[3])
An oral PCSK9 inhibitor developed by Merck & Co. (MSD) is a macrocyclic peptide molecule. It inhibits the interaction between PCSK9 and low-density lipoprotein receptors (LDLRs), allowing more LDLRs to return to the cell surface, ingesting more LDL cholesterol (LDL-C) from the bloodstream, and lowering LDL-C levels. In a Phase 1 clinical trial, the company's candidate therapy, MK-0616, was able to reduce LDL-C levels by about 65 percent. The specific structure of MK-0616 has not been officially released, and the structure of compound 44 associated with it has been released, and in preclinical studies it exhibits a PCSK9 binding capacity similar to that of the approved PCSK9 antibody. The review of the Drug Hunter website states that the discovery of such molecules represents a proof-of-concept for the rational design of oral macrocyclic polypeptide molecules.
Mirat's KRAS G12D inhibitor
Mirati developed MRTX1133 is a non-covalent reversible KRAS G12D inhibitor capable of binding to THE KRAS G12D mutant in an inactive and activated state, and exhibits a high specificity for the KRAS G12D mutant, which is more than 1000 times more selective to KRAS G12D than wild-type KRAS. In preclinical animal studies targeting multiple cancer types, MRTX1133 significantly reduced tumor size, especially in pancreatic cancer tumor models, where MRTX1133 responded in 8/11 (73%) pancreatic cancer models. The company plans to file an IND application with the U.S. FDA this year.
Takeda's EGFR exon 20 insertion mutation inhibitor
Takeda's oral tyrosine kinase inhibitor mobocertinib is an oral therapy specifically designed for EGFR exon 20 insertion mutations. It is a covalent inhibitor capable of generating covalent bonds with cysteine 797 at the EGFR active site, resulting in a sustained inhibition of EGFR enzymatic activity.
Last September, it received FDA approval for the treatment of non-small cell lung cancer patients carrying the EGFR exon 20 insertion mutation.
Eli Lilly targets GLP-1R molecular glue
LSN3318839 developed by Eli Lilly is a forward allogeneic modulator for glucagon-like peptide-1 receptor (GLP-1R). It, by binding to GLP-1R, will be able to enhance the activity of full-length GLP-1 polypeptides and their less potent metabolites. In vitro experiments have shown that the combination of LSN3318839 with less potent GLP-1 metabolites can achieve a glucose-dependent insulin secretion effect similar to that of full-length GLP-1. In animal models, LSN3318839, as a monotherapy or in combination with the dipeptidase 4 inhibitor sitagliptin, was able to significantly reduce blood glucose levels in animals. These results suggest that enhancing the activity of GLP-1R may achieve the goal of lowering hyperglycemia.
KRAS G12C inhibitor of Revolution Medicines
RM-018, developed by Revolution Medicines, is a small molecule inhibitor that inhibits the activity of KRAS G12C mutants by combining it with its activation state. One of the main reasons KRAS mutants are difficult to target is that they don't have a pocket on their surface that is suitable for binding to small molecule drugs. Revolution Medicines found that the activated KRAS protein, when bound to the chaperone protein cyclophilin A protein, was able to form a pocket that could be targeted by small molecule drugs. RM-018 can form a ternary complex with cyclophilin A protein and KRAS G12C protein to achieve the effect of inhibiting KRAS G12C activity.
This mechanism of action differs significantly from covalent inhibitors (e.g., Lumakras and adagrasib) that normally bind to the inactive state of KRAS G12C. Even if KRAS G12C mutants develop resistance to Lumakras and adagrasib, they may still be inhibited by RM-018.
Genentech's PI3Kα mutant degrader
Involisib (GDC-0077), developed by Roche's Genentech, is a selective inhibitor that targets the PI3Kα mutant. A study published by the company in Cancer Discovery showed that inavolisib can not only block the activity of PI3Kα, but also promote the degradation of the P110α catalytic subunit of pi3Kα mutant. Further research found that PI3Kα mutations that cause cancer make PI3Kα unstable, speeding up their degradation process. The combination of involisib and mutants makes them more unstable and easier to degrade. This dual mechanism of action gives involisib a stronger PI3Kα inhibition effect. It is currently being evaluated in Phase 3 clinical trials for the treatment of HR-positive, HER2-negative locally advanced or metastatic breast cancer patients with PI3KCA mutations in combination with other drugs.
Inavolisib (GDC-0077) can specifically degrade PI3Kα mutants (Image source: Genentech official website)
Oral RNA splicing regulator for H3 Biomedicine
RNA splicing is critical to cell function, and cells use complexes called spliceosomes to catalyze the excision of introns from RNA precursors, linking exons together to produce mature RNA. Many blood cancer cells develop mutations in an allele encoding splicing subunit proteins, meaning they rely more on the action of unmutated wild-type alleles. H3 Biomedicine's research therapy H3B-8800 is an oral RNA splicing regulator that targets the spliceosome SF3b complex. By inhibiting the action of the SF3b complex, tumor cells carrying splicing body mutations are more effectively killed. Currently, this RNA splicing regulator is being tested in a Phase 1 clinical trial to treat a variety of myeloid tumors.
Biocryst's oral kallikrein inhibitor
Orladeyo (berotralstat), an oral kallikrein inhibitor developed by Biocryst, was approved for marketing by the FDA in 2020 to prevent episodes of hereditary angioedema (HAE) in adults and pediatric patients older than 12 years of age. This is the first oral nonsteroidal treatment option to prevent episodes of HAE.
Genentech's estrogen receptor degrader
Genentech's investigative therapy giredestrant (GDC-9545) is a potential "best-in-class" selective estrogen receptor degrader (SERD). It has a unique mechanism of action that can inhibit er-mediated gene expression by binding to it before degrading the estrogen receptor (ER).