	US 12,214,047 B2
	FAP-activated proteasome inhibitors for treating solid tumors
William W. Bachovchin, Cambridge, MA (US); Hung-sen Lai, Andover, MA (US); and Sarah E. Poplawski, Belmont, MA (US)
Assigned to Trustees of Tufts College, Medford, MA (US)
Filed by Trustees of Tufts College, Medford, MA (US)
Filed on Jun. 15, 2021, as Appl. No. 17/348,043.
Application 17/348,043 is a continuation of application No. 16/688,574, filed on Nov. 19, 2019, granted, now 11,065,339.
Application 16/688,574 is a continuation of application No. 15/952,648, filed on Apr. 13, 2018, granted, now 10,517,955.
Application 15/952,648 is a continuation of application No. 15/167,109, filed on May 27, 2016, granted, now 9,956,297.
Application 15/167,109 is a continuation of application No. 14/241,666, granted, now 9,597,410, previously published as PCT/US2012/053140, filed on Aug. 30, 2012.
Claims priority of provisional application 61/528,824, filed on Aug. 30, 2011.
Prior Publication US 2021/0379190 A1, Dec. 9, 2021
This patent is subject to a terminal disclaimer.
Int. Cl. A61K 31/69 (2006.01); A61K 38/07 (2006.01); A61K 45/06 (2006.01); A61K 47/54 (2017.01); A61K 47/64 (2017.01); C07K 5/062 (2006.01); C07K 5/065 (2006.01); C07K 5/083 (2006.01); C07K 5/087 (2006.01); C07K 5/097 (2006.01); C07K 5/107 (2006.01); G01N 33/574 (2006.01); A61K 38/00 (2006.01)

CPC A61K 47/64 (2017.08) [A61K 31/69 (2013.01); A61K 38/07 (2013.01); A61K 45/06 (2013.01); A61K 47/54 (2017.08); C07K 5/06026 (2013.01); C07K 5/06034 (2013.01); C07K 5/06078 (2013.01); C07K 5/0806 (2013.01); C07K 5/0808 (2013.01); C07K 5/081 (2013.01); C07K 5/0812 (2013.01); C07K 5/0821 (2013.01); C07K 5/1016 (2013.01); G01N 33/574 (2013.01); A61K 38/00 (2013.01)]

21 Claims

1. A FAP-activated prodrug of a proteasome inhibitor represented by formula I:

A-B I

or a pharmaceutically acceptable salt thereof, wherein

A is Ser-(d)-Ala-Pro or (blocking group)-Ser-(d)-Ala-Pro, wherein the N-terminus of Ser is substituted with the blocking group;

B is

A and B being covalently linked by a bond that is enzymatically cleaved by FAP to release B in the free form; and

the prodrug has a k_cat/K_mfor FAP cleavage of the bond linking A and B of at least 10 fold more than for Prolyl endopeptidase EC 3.4.14.5 (PREP).