Table II.

Brain Distribution and Efflux Transporter Liability of some Molecular-targeted Therapeutic Agents for the Treatment of Brain Tumors

Molecular target	Compound	Species	Kp	fu,plasma	fu,brain	Kp,uu	P-gp substrate	BCRP substrate	Ref.
DNA alkylation	TMZ	mouse	0.56	NR	NR	NR	Yes	Yes	[99]
ATR	Berzosertib	mouse	0.64	0.081	0.0014	0.011	Yes	Yes	[73]
ATM	AZD1390	mouse	0.29	0.203	0.075	0.1	Yes	No	[100]
ATM	AZD1390	mouse	NR	NR	NR	0.04	Yes or no#	Yes or no#	[50]
ATM	AZD1390	Cynomolgus monkey	5.8*	0.175	0.01	0.33	NR	NR	[50]
ATM	WSD-0628	mouse	NR	0.0285	0.0269	0.3	No	No	[101]
DNA-PK	Peposertib	mouse	0.09	0.114	0.041	0.03	Yes	Yes	[49]
PARP	Pamiparib	rat	0.18	NR	NR	0.158	No	No	[102]
p53/MDM2	SAR405838	mouse	0.0275	0.00059	0.00015	0.007	Yes	No	[103]
p53/MDM2	BI-907828	mouse	0.009	0.0015	0.0003	0.002	Yes	No	[104]
EGFR	AEE788	mouse	0.066	0.068	0.029	0.029	Yes or no#	Yes or no#	[105]
EGFR	Afatinib	mouse	0.254	0.08	0.014	0.046	Yes	Yes	[105]
EGFR	AZD3759	mouse	1.7	0.058	0.101	2.96	No	No	[105]
EGFR	Dacomitinib	mouse	0.612	0.008	0.007	0.493	Yes or no#	Yes or no#	[105]
EGFR	Erlotinib	mouse	0.062	0.045	0.096	0.134	Yes	Yes	[105]
EGFR	Gefitinib	mouse	0.358	0.041	0.012	0.103	Yes	Yes	[105]
EGFR	Osimertinib	mouse	0.988	0.005	0.001	0.289	Yes	Yes	[105]
EGFR	Vandetanib	mouse	0.635	0.055	0.012	0.138	Yes	Yes	[105]
PDGFR-α	Ponatinib	mouse	0.82	0.0023	0.0003	0.11	Yes	Yes	[106]
PI3K	GNE-317	mouse	1.1	NR	NR	0.398	NR	NR	[107]
PI3K	Pictilisib	mouse	0.0127	NR	NR	0.0035	Yes	Yes	[107]
PI3K	GDC-0084	mouse	1.37	0.29	0.067	0.41	No	No	[108]
panRAF	CCT196969	mouse	0.006	0.001	0.005	0.03	Yes or no#	Yes or no#	[109]
panRAF	LY3009120	mouse	0.05	0.0182	0.0093	0.02	Yes or no#	Yes or no#	[109]
panRAF	MLN2480	mouse	0.2	0.0421	0.0098	0.05	Yes or no#	Yes or no#	[109]
MEK	E6201	mouse	2.66	0.026	0.0014	0.14	No	No	[75]
MEK	Trametinib	mouse	0.15	0.0021	0.0021	0.15	Yes or no#	Yes or no#	[75]
MEK	Cobimetinib	mouse	0.32	0.014	0.0012	0.027	Yes or no#	Yes or no#	[75]
KIF11	Ispinesib	mouse	0.23	0.06	0.005	0.02	Yes	Yes
Aurora A kinase	Alisertib	mouse	0.03	0.042	0.063	0.0044	Yes	No	[110]
CDK4/6	Abemaciclib	mouse	1.2	0.054	0.0079	0.17	Yes	Yes	[111]
CDK4/6	Palbociclib	mouse	0.1	0.23	0.02	0.01	Yes	Yes	[111]

^*yielded by PET data

^#substrate of P-gp and/or BCRP; NR, not reported

Kp: drug partition coefficient in the brain; fu,plasma: drug unbound fraction in plasma; fu,brain: drug unbound fraction in brain; Kp,uu: unbound drug partition coefficient in the brain