1,729,207 research outputs found
Development of PDE6D and CK1α Degraders through Chemical Derivatization of FPFT-2216
No full textImmunomodulatory
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
Development of PDE6D and CK1 Degraders through Chemical Derivatization of FPFT-2216
No full textImmunomodulatory
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
Block Card 2216 Chestnut Street
No full textThis image was produced by the Auditor's Office in Lucas County, Ohio for tax assessment purposes. Associated dates are approximate. Descriptive terms related to this photograph include: Shotgun houses | dwelling | 2216 Chestnut Street (Toledo, Ohio) | Extension of Elm Street Addition (Toledo, Ohio) | North Toledo (Toledo, Ohio
EC69-2216 The Papers in Your Life
Get PDFExtension Circular 69-2216: The papers in your life; suggestions for records keeping and important papers you need to carry with you
Block Card 2216 Elm Street
No full textThis image was produced by the Auditor's Office in Lucas County, Ohio for tax assessment purposes. Associated dates are approximate. Descriptive terms related to this photograph include: Shotgun houses | dwelling | 2216 Elm Street (Toledo, Ohio) | Elm Street Addition (Toledo, Ohio) | Digby Place (Toledo, Ohio) | Subdivision Ten | North Toledo (Toledo, Ohio
Block Card 2216 Westbrook Drive
No full textThis image was produced by the Auditor's Office in Lucas County, Ohio for tax assessment purposes. Associated dates are approximate. Descriptive terms related to this photograph include: dwelling | 2216 Westbrook Drive (Toledo, Ohio) | Garrison style | DeVeaux (Toledo, Ohio) | Extension of Mellwood (Toledo, Ohio
2216. Le Ménestrel d'Alfonse de Poitiers
No full text2216. Le Ménestrel d'Alfonse de Poitiers. In: Molinier Auguste. Les Sources de l'histoire de France - Des origines aux guerres d'Italie (1494). III. Les Capétiens, 1180-1328. Paris : A. Picard et fils, 1903. p. 5
Block Card 2216 Heatherwood Drive
No full textThis image was produced by the Auditor's Office in Lucas County, Ohio for tax assessment purposes. Associated dates are approximate. Descriptive terms related to this photograph include: Ranch houses | 2216 Heatherwood Drive (Toledo, Ohio) | Dwelling | Glen Arbor (Toledo, Ohio) | South Toledo Area (Toledo, Ohio
- …
