Manuscript alert! I’m excited to finally share our manuscript on PINCHs, now on bioRxiv:.

The work was spearheaded by Ella Livnah who almost single-handedly performed all of the experiments - herculean style, with invaluable feedback from co-corresponding author Emmanuel Levy who is a world-leader on protein symmetry and agglomeration.

These findings introduce a new paradigm in targeted protein degradation, with broad implications for chemical biology and therapeutic development. I’d welcome feedback from the community on this emerging modality.

- Functional advantages of PINCHs over their monomeric inhibitors, including, prolonged duration of action, and superior downregulation activity.- The concept of Hetero-PINCHs, enabling the simultaneous knockdown of two distinct homomeric proteins with a single molecule.

As a proof of concept, we demonstrate:.- Effective cellular downregulation of the clinically relevant homodimeric proteins BCL6 and Keap1.- In vitro polymerization studies validating the proposed mechanism.

This approach is entirely dependent on the presence of the target protein itself, bypassing key limitations of existing strategies such as PROTACs and molecular glues, which rely on recruiting additional cellular machinery.

By linking two identical ligands, each targeting a subunit of a homomeric protein complex, we induce polymer formation, ultimately leading to protein precipitation.

PINCHs (Polymerization Inducing Chimeras) are a new type of “TACs” and represent a novel approach to targeted protein knockdown, taking advantage of the intrinsic symmetry of homo-oligomeric proteins.

For the first time in written form, after numerous presentations in various meetings. This has been a long time in the making.

Combining covalent chemistry with proximity inducers expands their scope, and drives new discoveries. I tried to capture the state of the field in this (open access) comprehensive review. Good news - there are plenty of opportunities up for grabs :)

RT @ChemBioTalks: We are looking forward to the 4th Virtual ChemBio Talks with a full program with keynotes @KateCarrollLab and Kai Johnsso….

Check out the Kupcinet-Getz International Summer Program @WeizmannScience a great opportunity to visit and get a taste of science.

For the #covalent enthusiasts, check out the BPS "Emergence of irreversible modulation in drug discovery" meeting. Looks like a high local concentration of electrophiles :)

Such an elegant idea from the Gray lab! Target two nucleophiles simultaneously to reduce the probability of resistance mutation formation. Dielectrophiles were previously reported, but to my knowledge not in the context of avoiding resistance. Very cool.

RT @DanNomura: Covalent Hits and Where to Find Them - from ⁦@AstraZeneca⁩

RT @covid_moonshot: Our recent @ScienceMagazine article has been downloaded 24,806 times! So encouraging to see so much interest in our cro….

For those interested in #drugresistance check out this GRC co-chaired by @mitchell_sysbio

RT @FrankvonDelft: @XChem_DLS and @covid_moonshot and @asap_discovery leaving deep footprints. .

RT @EuroMedChem: 📢 Friedrich-Stolz Award Of The GDCh. For outstanding commitment, scientific discovery or innovative technology that contr….

RT @asap_discovery: The incredible @asap_discovery team members working with @XChem_DLS collected 14,631 X-ray datasets and deposited 6.7%….