Spotlight: Medicinal Chemistry Core

In this DF/HCC eNews Spotlight Edition, we present the DF/HCC Medicinal Chemistry Core which assists with all aspects of small molecule drug discovery, from the provision of suitable tool compounds to interrogate basic biology to the optimization of promising lead compounds for animal studies. The Core’s mission is to collaborate with researchers to advance their understanding of disease and accelerate the development of novel therapeutic agents.




• Medicinal chemistry consultation
- Input for grant applications, project screening strategies, HTS analysis
• Identification and provision of tool compounds
• Long-term drug discovery collaborations
- Optimization of hit compounds into advanced lead molecules with the potential for further development


MALT1 inhibitors for DLBCL
A collaboration between the groups of Gray (DFCI), Melnick (Weill Cornell Medical School) and Wu (BCH) to identify inhibitors of the paracaspase MALT1 as potential therapeutic agents for ABC-DLBCL. The project was a 3-year industry-funded collaboration. The core designed and synthesized small molecule inhibitors from two distinct chemical series, using both internal and CRO chemistry. 

  • Specific covalent inhibition of MALT1 paracaspase suppresses B cell lymphoma growth. Fontan, L. et al. J. Clin. Invest. (2018); 128, 4397-4412.
  • Peptide-based covalent inhibitors of MALT1 paracaspase. Hatcher, J. M. et al. Bioorg. Med. Chem. Lett. (2019); 29 (11), 1336-1339.
  • Quinoline and thiazolopyridine allosteric inhibitors of MALT1. Scott, D. A. et al. Bioorg. Med. Chem. Lett. (2019); 29 (14), 1694-1698. 


Targeted degradation of G12C KRas
The core collaborated with several labs at DFCI (Gray, Janne, Fischer) and UTSW (Westover) to explore the potential for KRas degradation through the preparation of PROTAC-type compounds from covalent G12C inhibitors.

  • Exploring targeted degradation strategy for oncogenic KRAS G12C. Zeng, M. et al. Cell Chem. Biol. (2020); 27, 19–31.


TNK2 inhibitors for genetically identifiable tumors
A collaboration between the Gray lab (DFCI) and a local biotech company to explore the utility of TNK2 inhibitors across a range of tumor types. Building upon an earlier report from the Gray lab of a potent and selective inhibitor, the core coordinated the design, synthesis and testing of over 300 new compounds. Synthesis was conducted at DFCI and at a chemistry CRO, with enzyme and PK testing at a partner CRO, and cell testing at either DFCI or the biotech.

  • Benzopyrimidodiazepinone inhibitors of TNK2. Groendyke, B. J. et al. Bioorg. Med. Chem. Lett. (2020); 30 (4), 126948.



For more information or to contact the Medicinal Chemistry Core, visit the core website here.