CK1α inhibitors(casein kinase 1 alpha 1 inhibitors), IKZF1 inhibitors(DNA-binding protein Ikaros inhibitors), IKZF3 inhibitors(Zinc finger protein Aiolos inhibitors)

Therapeutic Areas

Hemic and Lymphatic Diseases

Active Indication

Myelodysplastic Syndromes

Inactive Indication-

Originator Organization

Osaka University Immunology Frontier Research Center (IFREC)

Active Organization

Osaka University Immunology Frontier Research Center (IFREC)

Inactive Organization-

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

Structure/Sequence

Molecular FormulaC12H12N4O3S

InChIKeySKUSCUALKIOIST-UHFFFAOYSA-N

CAS Registry2367619-87-0

100 Clinical Results associated with FPFT-2216

100 Translational Medicine associated with FPFT-2216

100 Patents (Medical) associated with FPFT-2216

Literatures (Medical) associated with FPFT-2216

06 Feb 2024·Cancer research communications

FPFT-2216, a Novel Anti-lymphoma Compound, Induces Simultaneous Degradation of IKZF1/3 and CK1α to Activate p53 and Inhibit NFκB Signaling

Article

Author: Yamada, Mitsuo ; Satoyoshi, Hiroshi ; Kanaoka, Daiki ; Wakabayashi, Shota ; Nakanishi, Masato ; Kunimura, Naoshi ; Nishino, Satoko ; Ishii, Takafumi ; Urabe, Kazunori ; Yokoyama, Hironori

Abstract:

Reducing casein kinase 1α (CK1α) expression inhibits the growth of multiple cancer cell lines, making it a potential therapeutic target for cancer. Herein, we evaluated the antitumor activity of FPFT-2216—a novel low molecular weight compound—in lymphoid tumors and elucidated its molecular mechanism of action. In addition, we determined whether targeting CK1α with FPFT-2216 is useful for treating hematopoietic malignancies. FPFT-2216 strongly degraded CK1α and IKAROS family zinc finger 1/3 (IKZF1/3) via proteasomal degradation. FPFT-2216 exhibited stronger inhibitory effects on human lymphoma cell proliferation than known thalidomide derivatives and induced upregulation of p53 and its transcriptional targets, namely, p21 and MDM2. Combining FPFT-2216 with an MDM2 inhibitor exhibited synergistic antiproliferative activity and induced rapid tumor regression in immunodeficient mice subcutaneously transplanted with a human lymphoma cell line. Nearly all tumors in mice disappeared after 10 days; this was continuously observed in 5 of 7 mice up to 24 days after the final FPFT-2216 administration. FPFT-2216 also enhanced the antitumor activity of rituximab and showed antitumor activity in a patient-derived diffuse large B-cell lymphoma xenograft model. Furthermore, FPFT-2216 decreased the activity of the CARD11/BCL10/MALT1 (CBM) complex and inhibited IκBα and NFκB phosphorylation. These effects were mediated through CK1α degradation and were stronger than those of known IKZF1/3 degraders. In conclusion, FPFT-2216 inhibits tumor growth by activating the p53 signaling pathway and inhibiting the CBM complex/NFκB pathway via CK1α degradation. Therefore, FPFT-2216 may represent an effective therapeutic agent for hematopoietic malignancies, such as lymphoma.

Significance::

We found potential vulnerability to CK1α degradation in certain lymphoma cells refractory to IKZF1/3 degraders. Targeting CK1α with FPFT-2216 could inhibit the growth of these cells by activating p53 signaling. Our study demonstrates the potential therapeutic application of CK1α degraders, such as FPFT-2216, for treating lymphoma.

13 Jan 2022·Journal of medicinal chemistryQ1 · MEDICINE

Development of PDE6D and CK1α Degraders through Chemical Derivatization of FPFT-2216

Q1 · MEDICINE

Article

Author: Teng, Mingxing ; Sperling, Adam S. ; Ebert, Benjamin L. ; Gray, Nathanael S. ; Li, Yen-Der ; Donovan, Katherine A. ; Lu, Wenchao ; Sun, Jialin ; Nowak, Radosław P. ; Zhang, Tinghu ; Fischer, Eric S. ; Krupnick, Noah M.

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 CRL4^CRBN E3 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 KRAS^G12C-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.

13 Nov 2018·Proceedings of the National Academy of Sciences of the United States of AmericaQ1 · CROSS-FIELD

Humanized cereblon mice revealed two distinct therapeutic pathways of immunomodulatory drugs

Q1 · CROSS-FIELD

Article

Author: Metwally, Hozaifa ; Kang, Sujin ; Gemechu, Yohannes ; Sanchenkova, Ksenia ; Millrine, David ; Hashimoto, Shigeru ; Gyanu, Parajuli ; Kishimoto, Tadamitsu ; Prakash, Jaya

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 (CRBN^I391V) 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 CRBN^I391V mice responded with a higher degree of IKZF1 and CK-1α protein degradation. Furthermore, IMiDs resulted in an increase in IL-2 among CRBN^I391V mice 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.

100 Deals associated with FPFT-2216

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Indication	Highest Phase	Country/Location	Organization	Date
Myelodysplastic Syndromes	Preclinical	Japan	Osaka University Immunology Frontier Research Center (IFREC)	-

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