ISHC2015

7H-Pyrrolo[3,2-f]quinazoline-1,3-diamine (1) is a privileged chemical scaffold with significant biological activities. These include inhibition of dihydrofolate reductase (DHFR), protease-activated receptors (PAR) and protein tyrosine phosphatase 1B (PTP1B). However, the currently accessible chemical space derived from 1 is rather limited. In this presentation, we expanded the chemical space related to 1 by developing efficient methods for regioselective monoacylation at N1, N3 and N7, respectively. With this novel methodology, a focused library of mono-N-acylated pyrroloquinazoline-1,3-diamines were prepared and screened for anti-breast cancer activity. The structure-activity relationship (SAR) results showed that N3-acylated compounds were in general more potent than N1-acylated compounds while N7-acylation significantly reduced their solubility. Among the compounds evaluated, LBL1 possessed significantly more potent activity than 1 in MDA-MB-468 cells. More importantly, LBL1 was not toxic to normal human cells. Further chemical biology and mechanistic studies showed that LBL1 targets nuclear lamins to inhibit repair of double-strand DNA breaks (DSB) in breast cancer cells. The discovery of LBL1 as the first lamin-binding ligand from a focused novel library of 1 supports that 1 is a privileged scaffold. The availability of LBL1 should enable us to address the poorly understood molecular mechanisms of lamins in DSB repair processes