US 12,440,706 B2
Conjugated chemical inducers of degradation and methods of use
Peter Dragovich, South San Francisco, CA (US); Thomas Pillow, South San Francisco, CA (US); Robert Anthony Blake, South San Francisco, CA (US); and Ingrid Wertz, South San Francisco, CA (US)
Assigned to Genentech, Inc., South San Francisco, CA (US)
Filed by Genentech, Inc., South San Francisco, CA (US)
Filed on Apr. 23, 2021, as Appl. No. 17/239,086.
Application 17/239,086 is a continuation of application No. PCT/US2019/057878, filed on Oct. 24, 2019.
Claims priority of provisional application 62/749,812, filed on Oct. 24, 2018.
Prior Publication US 2023/0067037 A1, Mar. 2, 2023
Int. Cl. A61K 47/60 (2017.01); A61K 31/427 (2006.01); A61K 31/5517 (2006.01); A61K 31/661 (2006.01); A61K 47/68 (2017.01); A61P 35/00 (2006.01)
CPC A61K 47/6869 (2017.08) [A61K 31/427 (2013.01); A61K 31/5517 (2013.01); A61K 31/661 (2013.01); A61K 47/6803 (2017.08); A61P 35/00 (2018.01)] 17 Claims
OG exemplary drawing
 
1. A conjugate having the chemical structure:
Ab-(L1-D)p,
wherein,
D is a CIDE having the structure;
E3LB-L2-PB,
wherein:
E3LB is covalently bound to L1 and L2, having the structure of

OG Complex Work Unit Chemistry
 wherein custom character indicates the attachment point to L2 and custom character indicates the attachment point to L1;
L2 is a linker covalently bound to E3LB and PB;
PB is a protein binding group covalently bound to L2 and the PB binds BRD4 or Estrogen Receptor alpha (ERα), or variants, mutations, splice variants, indels or fusions thereof;
Ab is an antibody covalently bound to L1;
L1 is a linker covalently bound to the Ab and the E3LB, wherein L1 has the formula selected from the group consisting of:

OG Complex Work Unit Chemistry
wherein, R1 and R2 are independently selected from H and C1-C6 alkyl, or R1 and R2 together with the carbon to which each is attached form a 3, 4, 5, or 6-membered cycloalkyl or heterocyclyl group; R14a is H, haloalkyl, optionally substituted alkyl, methyl, fluoromethyl, hydroxymethyl, ethyl, isopropyl, or cyclopropyl; R15 is optionally substituted heteroaryl or optionally substituted aryl; and R is H, ethyl, isopropyl, tert-butyl, sec-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted hydroxyalkyl, optionally substituted heteroaryl, or haloalkyl; and
p has a value of from 1 to 8.