Macrocyclic Aminopyrimidines as Multitarget CDK and VEGF‐R Inhibitors with Potent Antiproliferative Activities

Abstract

X-ray structures from CDK2-aminopyrimidine inhibitor complexes led to the idea to stabilize the active conformation of aminopyrimidine inhibitors by incorporating the recognition site into a macrocyclic framework. A modular synthesis approach that relies on a new late-stage macrocyclization protocol that enables fast and efficient synthesis of macrocyclic aminopyrimidines was developed. A set of structurally diverse derivatives was prepared. Macrocyclic aminopyrimidines were shown to be multitarget inhibitors of CDK1/2 and VEGF-RTKs. In addition, potent antiproliferative activities toward various human tumor cells and a human tumor xenograft model were demonstrated.

Off‐Target Decoding of a Multitarget Kinase Inhibitor by Chemical Proteomics

“…[39] Due to the solvent accessibility of the sulfon-A C H T U N G T R E N N U N G amide moiety of C1, this group was identified as an appropriate site for compound immobilization in a chemical proteomics approach (Figure 1). After introducing a short linker at the sulfonamide group to give C1-SL, we immobilized this shortlinker analogue to a solid support and thereby generated a C1-matrix (Scheme 1).…”

“…Computational modeling: Based on cocrystallization experiments of CDK2 in complex with various C1 analogues, [39] C1 was modeled into the ATP binding pocket of CDK2 by using Discovery Studio 2.1 (Accelrys, Cambridge, UK). The solvent-accessible surface was calculated by using PyMOL (DeLano Scientific LLC, Palo Alto, CA, USA).…”

“…This inhibitor was previously shown to have high potency against CDK2, and macrocyclic derivatives were described as multitarget CDK and VEGF-R inhibitors with potent antiproliferative activities towards various human tumor cells and in a human tumor xenograft model. [39] Based on a computational model of a compound-target complex, we carried out two different immobilization routes that were aimed at uncovering potential off-targets that interact with distinct compound moieties. Furthermore, we generated a soluble mimic of the immobilized inhibitor to confirm that immobilization of the compound does not interfere with its functionality.…”

Sulfoximine: Eine vernachlässigte Chance in der medizinischen Chemie

“…Dieser Vorschlag stieß anfangs auf große Skepsis, doch die Sulfoximin-Modellverbindung 34 zeigte signifikante CDK-inhibitorische Eigenschaften und eine moderate antiproliferative Aktivität. [42] Darüber hinaus wies die Verbindung keine CA-inhibitorischen Eigenschaften auf. Eine umfangreiche Leitstrukturoptimierung in dieser neuen Klasse von Sulfoximin-CDKInhibitoren führte schließlich zur Identifizierung von BAY 1000394 (Abbildung 10).…”

“…Eine umfangreiche Leitstrukturoptimierung in dieser neuen Klasse von Sulfoximin-CDKInhibitoren führte schließlich zur Identifizierung von BAY 1000394 (Abbildung 10). [43] Bei dieser Verbindung handelt es sich um einen nanomolaren pan-CDK-Inhibitor mit sehr potenter antiproliferativer Aktivität, der jedoch keine Off- Target Sulfoximine als Entwicklungskandidat ausgewählt und ist derzeit Gegenstand einer klinischen Phase-I-Studie an Patienten mit fortgeschrittenen soliden Tumoren (Studiennummer bei clinicaltrials.gov: NCT01188252). [3] BAY 1000394 ist seit langer Zeit das erste Sulfoximin in der klinischen Entwicklung.…”