1. Development of PDE6D and CK1α Degraders through Chemical Derivatization of FPFT-2216
Wenchao Lu, Nathanael S Gray, Adam S Sperling, Benjamin L Ebert, Tinghu Zhang, Mingxing Teng, Katherine A Donovan, Eric S Fischer, Jialin Sun, Radosław P Nowak, Yen-Der Li, Noah M Krupnick J Med Chem . 2022 Jan 13;65(1):747-756. doi: 10.1021/acs.jmedchem.1c01832.
Immunomodulatory drugs are a class of drugs approved for the treatment of multiple myeloma. These compounds exert their clinical effects by inducing interactions between the CRL4CRBNE3 ubiquitin ligase and a C2H2 zinc finger degron motif, resulting in degradation of degron-containing targets. However, although many cellular proteins feature the degron motif, only a subset of those are degradable via this strategy. Here, we demonstrated that FPFT-2216, a previously reported "molecular glue" compound, degrades PDE6D, in addition to IKZF1, IKZF3, and CK1α. We used FPFT-2216 as a starting point for a focused medicinal chemistry campaign and developed TMX-4100 and TMX-4116, which exhibit greater selectivity for degrading PDE6D and CK1α, respectively. We also showed that the region in PDE6D that interacts with the FPFT-2216 derivatives is not the previously pursued prenyl-binding pocket. Moreover, we found that PDE6D depletion by FPFT-2216 does not impede the growth of KRASG12C-dependent MIA PaCa-2 cells, highlighting the challenges of drugging PDE6D-KRAS. Taken together, the approach we described here represents a general scheme to rapidly develop selective degraders by reprogramming E3 ubiquitin ligase substrate specificity.
2. Humanized cereblon mice revealed two distinct therapeutic pathways of immunomodulatory drugs
David Millrine, Hozaifa Metwally, Shigeru Hashimoto, Ksenia Sanchenkova, Jaya Prakash, Sujin Kang, Parajuli Gyanu, Yohannes Gemechu, Tadamitsu Kishimoto Proc Natl Acad Sci U S A . 2018 Nov 13;115(46):11802-11807. doi: 10.1073/pnas.1814446115.
Immunomodulatory drugs (IMiDs), including thalidomide derivatives such as lenalidomide and pomalidomide, offer therapeutic benefit in several hematopoietic malignancies and autoimmune/inflammatory diseases. However, it is difficult to study the IMiD mechanism of action in murine disease models because murine cereblon (CRBN), the substrate receptor for IMiD action, is resistant to some of IMiDs therapeutic effects. To overcome this difficulty, we generated humanized cereblon (CRBNI391V) mice thereby providing an animal model to unravel complex mechanisms of action in a murine physiological setup. In our current study, we investigated the degradative effect toward IKZF1 and CK-1α, a target substrate of IMiDs. Unlike WT mice which were resistant to lenalidomide and pomalidomide, T lymphocytes from CRBNI391Vmice responded with a higher degree of IKZF1 and CK-1α protein degradation. Furthermore, IMiDs resulted in an increase in IL-2 among CRBNI391Vmice but not in the WT group. We have also tested a thalidomide derivative, FPFT-2216, which showed an inhibitory effect toward IKZF1 protein level. As opposed to pomalidomide, FPFT-2216 and lenalidomide degrades CK-1α. Additionally, we assessed the potential therapeutic effects of IMiDs in dextran sodium sulfate (DSS)-induced colitis. In both WT and humanized mice, lenalidomide showed a significant therapeutic effect in the DSS model of colitis, while the effect of pomalidomide was less pronounced. Thus, while IMiDs' degradative effect on IKZF1 and CK-1α, and up-regulation of IL-2, is dependent on CRBN, the therapeutic benefit of IMiDs in a mouse model of inflammatory bowel disease occurs through a CRBN-IMiD binding region independent pathway.
