📢The Zheng Lab @hms-bcmp.bsky.social is recruiting a Postdoctoral Fellow in organic chemistry & chemical biology to develop covalent chemistry and cancer therapeutics.

🔬Website: sites.harvard.edu/zheng/
📧Contact: qinheng_zheng@hms.harvard.edu
Apply via👉 academicpositions.harvard.edu/postings/15510

[9/10] Tianfang used modeling and synthesis to design G13Ci-22, a register-shifted acrylamide optimized for geometry & reactivity. G13Ci-22 targets both on- and off-state K-Ras(G13C) and locks the super exchanger mutant at a signaling-incompetent state.

[7/10] We showed that a classic esterification can be repurposed to selectively label the oncogenic Asp12 in K-Ras(G12D). Diazo-G12Di-1, a Switch-II Pocket ligand inspired by natural product azaserine, potently and selectively inhibited proliferation of G12D-mutant cancer cells.

[5/10] The observed covalent efficiency stems not just from proximity—but precise pre-reactive geometry, which was not foreseen during design. The β-lactone warhead showed a steep SAR: subtle changes dramatically altered reactivity. Balancing reactivity & metabolic stability remains a challenge.

[3/10] These compounds opened new opportunities and also raised new questions:
1. Why did β-lactones work, and what are their limits?
2. What’s alternative chemistry for targeting Asp12?
3. Can we go beyond G12 to other hotspot mutants?
Here’s what we found👇

🧵[1/10] A busy week for K-Ras! We reported three stories on covalent, mutant-selective targeting of oncogenic K-Ras mutations @pubs.acs.org. Covalent chemistry has been key in drugging this once “undruggable” GTPase. Sotorasib and adagrasib are the only approved therapeutics for K-Ras(G12C).