Targeting Medium-Chain Acyl-CoA Dehydrogenase (MCAD) for Glioblastoma (GBM)
Developing potent, selective MCAD inhibitors
Hits identified by high-throughput screen of 278k compounds based on RF-MS.
MCAD structures with screening hits guides small molecule optimization.
Example of a partially optimized screening hit with cellular potency < 1 µM.
Crystal structure of MCAD:Octanoyl-CoA
Properties
CmpdID: 75915
MCAD IC 50 (nM)
37
Octanoyl-CoA (substrate)
SCAD IC 50 (nM)
>5,600
LCAD IC 50 (nM)
>5,600
VLCAD IC 50 (nM)
>5,600
Flavin adenine dinucleotide (FAD, cofactor)
MCAD CETSA IC 50 (nM)
~200
MCAD OCCT (nM)
540
Pampa Pe (x10 -6 cm/s (% rec))
11(60%)
100
Plasma St. (m/r/d/h t 1/2 min)
330/100/360/99
Cryo-EM structure of MCAD
MW/cLogP/TPSA
459/2.28/116
50
MPO/BBB
3.83/3.16
0
Refined map at 3.3 Å Using 88k particles
F Yu 1 , P Leonard 1 , M Hamilton 1 , F Puca 2 , N Pham 2 , N Rogers 1 , F Alvarez 1 , C Rodriguez 1 , V Nair 1 , N Akkaladevi 1 , R Thapar 1 , S Vaccaro 1 , A Mendiola 1 , Q Xu 1 , M Geck Do 1 , J Cross 1 , M Soth 1 , Y Jiang 1 , G Draetta 2 , and P Jones 1
0.0001
0.01
1
100
Conc. (nM)
IACS-050595-000-2, IC50 = 1000 nM IACS-075710-000-1, IC50 = 55 nM IACS-135587-000-1, IC50 = 8238 nM
1 Institute for Applied Cancer Science 2 Department of Genomic Medicine
Nov. 17-18, 2022
3
MD Anderson Cancer Center
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