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1 A B S T R A C T P r o x i m i t y i n d u c i n g d r u g s o f f e r t r a n s f o r m a t i v e t h e r a p e u t i c o p p o r t u n i t i e s b y p r e c i s e l y c o n t r o l l i n g p r o t e i n i n t e r a c t i o n s a n d /o r p r o t e i n m o d u l a t i o n s i n c l u d i n g t a r g e t e d p r o t e i n d e g r a d a t i o n . P R O TA C s , p r o m i n e n t i n t h i s f i e l d , s u c c e s s f u l l y d e g r a d e p r e v i o u s l y u n d r u g g a b l e p r o t e i n s l i k e t r a n s c r i p t i o n f a c t o r s b y e n g a g i n g b o t h t a r g e t p r o t e i n s a n d E 3 l i g a s e s . D e s p i t e t h e i r m o d u l a r d e s i g n h o w e v e r , P R O TA C s f a c e c h a l l e n g e s d u e t o l a r g e m o l e c u l a r s i z e , l i p o p h i l i c i t y , p o o r b i o a v a i l a b i l i t y , a n d t o x i c i t y . M o l e c u l a r g l u e s p r e s e n t a p r o m i s i n g a l t e r n a t i v e , o v e r c o m i n g t h e s e l i m i t a t i o n s w i t h s m a l l e r s i z e a n d i m p r o v e d b i o a v a i l a b i l i t y . Y e t , i d e n t i f y i n g a n d o p t i m i z i n g g l u e s i s m o r e c h a l l e n g i n g , a s t h e i r b i n d i n g i n t e r a c t i o n s a r e s t i l l u n p r e d i c t a b l e . I n t h i s c a s e s t u d y , D r . H a n s - J ör g R o t h , f o r m e r d i r e c t o r a t N o v a r t i s G l o b a l D i s c o v e r y C h e m i s t r y , e m p h a s i z e s o p t i m i z i n g c o o p e r a t i v i t y — b o o s t i n g t a r g e t a f f i n i t y v i a c h a p e r o n e p r o t e i n s — a s t h e k e y t o d e v e l o p i n g s m a l l e r , h i g h l y s e l e c t i v e , a n d s a f e r p r o x i m i t y - i n d u c i n g t h e r a p e u t i c s . U S E R E X P E R I E N C E C A S E S T U D Y P R O X I M I T Y I N D U C I N G T H E R A P E U T I C S Proximity Inducers in Drug Discovery - A Perspective on Cooperativity An interview with Dr. Hans-Jörg Roth Former Director of Global Discovery Chemistry at Novartis K E Y W O R D S Proximity Inducers, Molecular Glues, Affinity, Cooperativity, Screening, Spectral Shift Technology, PROTACs, Degradation.