917918-81-1Relevant articles and documents
Antibody Conjugation of a Chimeric BET Degrader Enables in vivo Activity
Pillow, Thomas H.,Adhikari, Pragya,Blake, Robert A.,Chen, Jinhua,Del Rosario, Geoffrey,Deshmukh, Gauri,Figueroa, Isabel,Gascoigne, Karen E.,Kamath, Amrita V.,Kaufman, Susan,Kleinheinz, Tracy,Kozak, Katherine R.,Latifi, Brandon,Leipold, Douglas D.,Sing Li, Chun,Li, Ruina,Mulvihill, Melinda M.,O'Donohue, Aimee,Rowntree, Rebecca K.,Sadowsky, Jack D.,Wai, John,Wang, Xinxin,Wu, Cong,Xu, Zijin,Yao, Hui,Yu, Shang-Fan,Zhang, Donglu,Zang, Richard,Zhang, Hongyan,Zhou, Hao,Zhu, Xiaoyu,Dragovich, Peter S.
supporting information, p. 17 - 25 (2019/11/20)
The ability to selectively degrade proteins with bifunctional small molecules has the potential to fundamentally alter therapy in a variety of diseases. However, the relatively large size of these chimeric molecules often results in challenging physico-chemical properties (e. g., low aqueous solubility) and poor pharmacokinetics which may complicate their in vivo applications. We recently discovered an exquisitely potent chimeric BET degrader (GNE-987) which exhibited picomolar cell potencies but also demonstrated low in vivo exposures. In an effort to improve the pharmacokinetic properties of this molecule, we discovered the first degrader-antibody conjugate by attaching GNE-987 to an anti-CLL1 antibody via a novel linker. A single IV dose of the conjugate afforded sustained in vivo exposures that resulted in antigen-specific tumor regressions. Enhancement of a chimeric protein degrader with poor in vivo properties through antibody conjugation thereby expands the utility of directed protein degradation as both a biological tool and a therapeutic possibility.
Preparation of the HIV Attachment Inhibitor BMS-663068. Part 1. Evolution of Enabling Strategies
Fox, Richard J.,Tripp, Jonathan C.,Schultz, Mitchell J.,Payack, Joseph F.,Fanfair, Dayne D.,Mudryk, Boguslaw M.,Murugesan, Saravanababu,Chen, Chung-Pin H.,La Cruz, Thomas E.,Ivy, Sabrina E.,Broxer, Sévrine,Cullen, Ryan,Erdemir, Deniz,Geng, Peng,Xu, Zhongmin,Fritz, Alan,Doubleday, Wendel W.,Conlon, David A.
, p. 1095 - 1109 (2017/08/23)
The development of two enabling routes that led to the production of >1000 kg of BMS-663068 (3) is described. The route identified for the initial 100 kg delivery to support development activities and initial clinical trials involved the conversion of 2-amino-4-picoline to the parent active pharmaceutical ingredient (API), followed by pro-drug installation and deprotection. To eliminate the problematic isolation of the parent API and synthesis of di-t-butyl(chloromethyl)phosphate, a second-generation pro-drug installation route was developed which involved the conversion of a late-stage common intermediate to an N(1)-thioether derivative followed by chloromethylation, displacement with di-t-butylpotassium phosphate, and deprotection. This second strategy resulted in the multikilogram scale preparation of the API in 14 linear steps and ～7% overall yield.
