TMX-4116
目录号 : GC64131TMX-4116 是酪蛋白激酶 1α (CK1α) 降解剂。TMX-4116 在 MOLT4、Jurkat 和 MM.1S 细胞中显示出对 CK1α 的降解偏好,DC50 小于 200 nM。TMX-4116 可用于多发性骨髓瘤的研究。
Cas No.:2766385-56-0
Sample solution is provided at 25 µL, 10mM.
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TMX-4116 is a casein kinase 1α (CK1α) degrader. TMX-4116 shows the degradation preference for CK1α with DC50s less than 200 nM in MOLT4, Jurkat, and MM.1S cells. TMX-4116 can be used for the research of multiple myeloma[1].
TMX-4116 (compound 16; 1 μM; 4 h) shows a high degradation preference for CK1α in MOLT4 cells[1].TMX-4116 (250 nM, 4 h) induces primary target degradation of CK1α, while no downregulation of PDE6D, IKZF1, and IKZF3 in MOLT4 cells[1].
[1]. Teng M, et al. Development of PDE6D and CK1α Degraders through Chemical Derivatization of FPFT-2216. J Med Chem. 2022 Jan 13;65(1):747-756.
Cas No. | 2766385-56-0 | SDF | Download SDF |
分子式 | C17H19N5O4S | 分子量 | 389.43 |
溶解度 | DMSO:100mg/mL(256.79 mM; ultrasonic and warming and heat to 60°C) | 储存条件 | Store at -20°C |
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Development of PDE6D and CK1α Degraders through Chemical Derivatization of FPFT-2216
J Med Chem 2022 Jan 13;65(1):747-756.PMID:34965125DOI: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 CRL4CRBN 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 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.