Targeting Medium-Chain Acyl-CoA Dehydrogenase for Glioblast…

Targeting Medium-Chain Acyl-CoA Dehydrogenase (MCAD) for Glioblastoma (GBM) MCAD as a key vulnerability unique to GBM identified by an in vivo functional genomic screen

GBM is the most common and aggressive primary brain cancer, with about 12,000 new diagnoses each year.

A functional genomic screen of metabolism genes in an in vivo model using patient-derived GBM cells (GSCs) uncovered importance of enzymes involved in fatty acid oxidation.

Elevated expression of MCAD in patient GBM samples vs. normal brain.

Malignant Brain Tumor Statistics, 2021

ACADM mRNA levels in glioma subtypes vs. normal brain (TCGA data set).

Immunohistochemistry for MCAD on tissue microarray derived from normal brain and GBM tissue

Not much improvement in survival since 1975 for elders

Scale bars, 100 μm for × 4 and 25 μm for × 20.

CA: A Cancer J Clinicians , 71(5): 381-406. DOI: 10.3322/caac.21693. Cancer Discov, 11(11): 2904-2923. DOI: 10.1158/2159-8290.CD-20-1437.

Year of diagnosis

Nov. 17-18, 2022

1

MD Anderson Cancer Center

Targeting Medium-Chain Acyl-CoA Dehydrogenase (MCAD) for Glioblastoma (GBM) Downregulation of MCAD resulted in severe mitochondrial failure in GBM and longer animal survival

MCAD-knockdown dramatically attenuated tumor growth using GSC8.11 and GSC6.27.

Downregulation of MCAD impaired mitochondrial function

Lipid accumulation and reactive oxygen species (ROS)-related damage in MCAD-knockdown GSCs

GSC 6.27

GSC 8.11

oxygen consumption rate significantly decreased in basal respiration and reserve respiratory capacity in ACADM -deleted GSCs

GSC 8.11 xenograft tumor tissues showed lipid accumulation upon ACADM silencing

12 weeks

4 weeks

4 weeks

8 weeks

- DOX

+ DOX

MCAD-knockdown significantly extended survival time.

MCAD-knockdown GSC 8.11 partially rescued in fatty acid free medium (left) and by GSH (right)

decrease in ATP content in MCAD-depleted GSCs

GSC 8.11

P= *0.0321 *0.0164

sh-ctrl

ATP

100

1.5

GSC 8.11

sh-ACADM1

sh-ctrl sh-ctrl + GSH sh-ACADM1 sh-ACADM1 + GSH

150000

**

**

sh-ACADM2

100000

1.0

50

50000

0.5

*

*

P< 0.0001

0

0

2

4

6

7

0

Time (Days)

0.0

Time (weeks) 4 6 8 10 12 14

sh-ctrl

sh-ACADM1 sh-ACADM2

Nov. 17-18, 2022

2

MD Anderson Cancer Center

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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