Table 2 Cellular cytotoxic response to agents with likely CNS exposure and cellular activity in DIPG.

Drug nameMechanism
of action
Development
phase*
MPO
score
CNS
penetrant
JHH-DIPG-1§SU-DIPG-XIII§SU-DIPG-XVII§SU-DIPG-XXV§
ColchicineTub. pol. inhibitorApproved5.47Unknown0.029 μM0.052 μM0.030 μM0.041 μM
PlinabulinTub. pol. inhibitorPhase 35.03Yes0.052 μM0.166 μM0.037 μM0.047 μM
Combretastatin A-4Tub. pol. inhibitorPhase 25.36Yes0.010 μM0.018 μM0.007 μM0.010 μM
AzixaTub. pol. inhibitorPhase 25.08Yes0.011 μM0.009 μM0.008 μM0.006 μM
SepantroniumSurvivin inhibitor.Preclinical5.63Unknown0.104 μM0.002 μM0.009 μM0.026 μM
MarizomibProteasome
inhibitor
Phase 15.50Yes0.029 μM0.014 μM0.033 μM0.018 μM
PI-103PI3K inhibitorPreclinical5.40Unknown5.254 μM0.332 μM0.525 μM0.186 μM
DaporinadNAMPT inhibitorPhase 15.09Yes0.004 μM0.002 μM0.012 μM0.005 μM
NAMPT-IN-1NAMPT inhibitorPreclinical4.45Unknown0.047 μM0.037 μM0.263 μM0.083 μM
GMX-1778NAMPT inhibitorPreclinical5.16Unknown0.015 μM0.008 μM0.030 μM0.013 μM
GDC-0623MEK inhibitorPhase 14.49Yes0.105 μM0.148 μM0.148 μM0.331 μM
AZD-8330MEK inhibitorPhase 24.44Unknown0.059 μM0.132 μM0.166 μM0.296 μM
TriptolideXBP inhibitorPhase 25.75Yes0.083 μM0.105 μM0.186 μM0.209 μM
TriptonideXBP inhibitorPreclinical6.00Yes0.132 μM0.263 μM0.296 μM0.372 μM
GanetespibHSP90 inhibitorPhase 25.16Yes0.066 μM0.042 μM0.037 μM0.037 μM
HSP-990HSP90 inhibitorPreclinical4.92Unknown0.037 μM0.042 μM0.030 μM0.030 μM
NSC-319726Oxidative stressPreclinical5.75Unknown0.026 μM0.024 μM0.009 μM0.013 μM
ElesclomolOxidative stressPhase 15.21Unknown0.005 μM0.009 μM0.019 μM0.019 μM
DinaciclibCDK inhibitorPhase 15.20Yes0.042 μM0.037 μM0.037 μM0.030 μM
CGP-60474CDK inhibitorPreclinical5.16Unknown0.118 μM0.083 μM0.132 μM0.132 μM
SB-1317CDK inhibitorPhase 24.54Unknown0.166 μM0.132 μM0.083 μM0.093 μM
PodofiloxTopo II inhibitorApproved5.27Unknown0.030 μM0.030 μM0.042 μM0.047 μM

Notes: Agents with an MPO score above 4.0 and an average Z-AUC below −1.9.

*Highest achieved clinical phase in any indication at the time of publication.

†The CNS MPO scores are based on the design algorithm defined by Wager et al. (18).

‡Outcome definitions: “Yes” means that published results confirmed CNS exposure in animal or human studies. “Unknown” means that published results were not available to the best of our knowledge.

§AC50 values are provided for agents with Z-AUC values < −0.85 and are based on the NCATS curve generator and are only provided for agents with a curve class designation of −1.1, −1.2, or −2.1 [see (43) for curve class definitions].

‖This agent is in active clinical evaluation as a prodrug named Minnelide.