2. Early Degrader Optimization.

compound	R 1	R 2	X	MKN1 CDK2 DC50 /D max	MDCK-WT Papp/MDR1 ER	logD7.4/FaSSIF	calc. minE 3D-PSA	HLM/RLM clint	rat PK (Cl, Vss, T 1/2, %F)
8	H	H	H	4.9/90%	1.0/>30	4.1, 153	286	79/<21	59/15/5.7/1%
9	H	H	F	12/86%	2.0/>54	4.6, 173	233	102/26	45/11/4.9/5%
10	(R)-Me	H	F	13/85%	1.5/>530	5.7, 110	219	181/<21	4/1/2.8/10%
11	(S)-Me	H	F	200/63%	3.1/>230	5.6, 115	218	96/<21	13/2/3.5/33%
12	Rac-Me	D	F	39/72%	2.4/>26	4.9, 131		118/<21	6/2/3.1/29%
13				1/95%	2.3/91	4.6, 62		143/25

^aUnits of nM.

^bUnits of 10^–6 cm/s.

^cUnits of μM.

^dSee the Supporting Information for details.

^eUnits of mL/min/kg.

^fIV (2 mg/kg)/PO (10 mg/kg), Cl in units of mL/min/kg, V_ss in units of L/kg, T _1/2 in units of h.