An Anilinoquinazoline Derivative Inhibits Tumor Growth through Interaction with hCAP-G2, a Subunit of Condensin II

Abstract

We screened 46 novel anilinoquinazoline derivatives for activity to inhibit proliferation of a panel of human cancer cell lines. Among them, Q15 showed potent in vitro growth-inhibitory activity towards cancer cell lines derived from colorectal cancer, lung cancer and multiple myeloma. It also showed antitumor activity towards multiple myeloma KMS34 tumor xenografts in lcr/scid mice in vivo. Unlike the known anilinoquinazoline derivative gefitinib, Q15 did not inhibit cytokine-mediated intracellular tyrosine phosphorylation. Using our mRNA display technology, we identified hCAP-G2, a subunit of condensin II complex, which is regarded as a key player in mitotic chromosome condensation, as a Q15 binding partner. Immunofluorescence study indicated that Q15 compromises normal segregation of chromosomes, and therefore might induce apoptosis. Thus, our results indicate that hCAP-G2 is a novel therapeutic target for development of drugs active against currently intractable neoplasms.

MIP-2A Is a Novel Target of an Anilinoquinazoline Derivative for Inhibition of Tumour Cell Proliferation

“…4B). As we have previously reported, the cleavage of PARP was detected by treatment with Q15 [2]. Furthermore, the c-Myc protein level also decreased in a Q15 concentration-dependent manner and correlated with the extent of PARP cleavage.…”

“…As shown in Figure S1, we found a negative correlation (correlation coefficient = −0.62) between expression level of c-Myc and sensitivity to Q15 in several cell lines we previously tested [2]. Five of the six Q15-sensitive cell lines (IC 50  = 1.1−5.1), KMM1, KMS11, KMS34, RPMI8226, and SW480, expressed high levels of c-Myc, while HeLa cells had a low c-Myc expression level.…”

“…Q15 showed a more potent activity than gefitinib [13], a well-established anilinoquinazoline derivative with a potent activity against non-small-cell lung tumours. Furthermore, we also reported that Q15 interacts with hCAP-G2, a subunit of the condensin II complex, and thereby induces a structural aberration of the chromosome in mitosis, leading to abnormal cell division [2]. However, whether such a defect in normal cell division is directly linked to apoptosis remains to be determined.…”

“…In our recent study, Q15 was identified as a novel anilinoquinazoline derivative that represses the proliferation of several types of tumour cell lines, including intractable tumours [2]. Q15 showed a more potent activity than gefitinib [13], a well-established anilinoquinazoline derivative with a potent activity against non-small-cell lung tumours.…”

“…1A), as a novel compound showing potent antitumor activity [2]. Additionally, using an mRNA display method [3]–[5], we identified hCAP-G2, a subunit of condensin II as a Q15-binding protein and confirmed that Q15 binds to the condensin II complex; accordingly, hCAP-G2 may affect chromosomal segregation in mitosis, leading to abnormal cell division and cell death [2]. However, it remains controversial whether only abnormal cell division caused by inhibition of condensin II leads to cell death.…”