Alzheimer's disease is an irreversible neurodegenerative disorder that is characterized by the abnormal aggregation of amyloid-β into neurotoxic oligomers and plaques. Although many disease-modifying molecules are currently in Alzheimer clinical trials, a small molecule that inhibits amyloid-β aggregation and ameliorates the disorder has not been approved to date. Herein, we report the effects of a potent small molecule, 6-methoxy-2-(4-dimethylaminostyryl) benzofuran (KMS88009), that directly disrupts amyloid-β oligomerization, preserving cognitive behavior when used prophylactically and reversing declines in cognitive behavior when used therapeutically. KMS88009 exhibited excellent pharmacokinetic profiles with extensive brain uptake and a high level of safety. When orally administered before and after the onset of Alzheimer's disease symptoms, KMS88009 significantly reduced assembly of amyloid-β oligomers and improved cognitive behaviors in the APP/PS1 double transgenic mouse model. The unique dual mode of action indicates that KMS88009 may be a powerful therapeutic candidate for the treatment of Alzheimer's disease.

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A novel series of thieno[3,2-d]pyrimidine derivatives were synthesised and their inhibitory effects against diacylglycerol acyltransferase 1 (DGAT-1) were assessed. cis-Isomer 17a showed potent and selective inhibitory activity against DGAT-1 in SF9 cells. In addition, 17a had an acceptable pharmacokinetic profile and accumulated mainly in the small intestine and liver. Oral administration of 17a led to a significant reduction in plasma triacylglycerol level during an oral lipid tolerance test (OLTT) in murine and canine models. Taken together, 17a is a high-quality candidate that deserves further investigation.

Cyclin‐dependent kinase (CDK) 9 is a protein kinase that plays a major regulatory role in the process of transcription, thereby representing an attractive target in cancer therapy. A series of novel, highly potent, selective derivatives (coined compounds 8–15) were designed, synthesized, and evaluated for their inhibitory effect on CDK functions using cancer cell lines. Here, we showed that our compound 8 exhibited a potent CDK9 inhibitory activity in ICR mice, with an IC50 value of 2.3 nM as well as favorable pharmacokinetic properties. Using an MV4‐11 xenograft mouse model, compound 8 showed antitumor efficacy at a dose of 10 mg/kg; compound 8 treatment was well tolerated, with no adverse effects on body weight or animal health. Our in vitro and in vivo findings strongly suggest that compound 8 holds great promise for the development of highly potent CDK9 inhibitors in anticancer approaches.

Either enhancer of zeste homolog 2 (EZH2) or its homolog EZH1, the enzymatic core subunit of polycomb repressive complex 2 (PRC2), acts an essential role for the maintenance of transcriptional repression by the methylation of histone H3 lysine 27 (H3K27). EZH2 gain-of-function (GOF) mutations (e.g. Y641, A677, and A687) or wild-type activation cause an increased activity leading to hyperinduce trimethylation of H3K27 (H3K27me3). Meanwhile, loss-of-function (LOF) mutation of major components (e.g. ARID1A, PBRM1, INI1) in chromatin remodeling complex, SWItch/Sucrose Non-Fermentable (SWI/SNF), results in a loss of its ability to oppose PRC2 and subsequently activation of EZH2. Accordingly, the dysfunctions of EZH2 or the alterations of regulatory SWI/SNF complex proteins have been reported to be associated with the development and progression of a variety of malignant tumors. Although PRC2 is suppressed by EZH2 inhibition, the activity of EZH1 is complementarily increased to replace the role of EZH2. Consequently, dual inhibition of EZH1 and EZH2 could be more effective than EZH2 inhibition alone in blocking PRC2 function as an anti-cancer therapy. Thus, we have developed a novel EZH1/2 dual inhibitor, HM97662, which simultaneously inhibited the methyltransferase activity of wild-type EZH1 as well as wild-type and GOF mutant EZH2 at nanomolar concentrations. Herein, we presented that HM97662, having enhanced EZH1 inhibitory activity compared to EZH2 inhibitors currently approved or in clinical development, potently and dose-dependently decreased global H3K27me3 in cancer cells. HM97662 showed broader and stronger anti-proliferative activities against various hematological cancer cell lines with EZH2 activating mutations as well as solid tumor cell lines with negatively mutated components of regulatory protein complexes. At this time, it was confirmed in the MCL cell line that HM97662, unlike the EZH2 selective inhibitor, does not cause the elevation of EZH1. HM97662 was observed to effectively modulate cell cycle arrest and induce apoptotic markers in a dose-dependent manner, as well as decrease intracellular H3K27me3, a pharmacodynamic marker, even at low concentration. As a result, HM97662 inhibited tumor growth more effectively than known EZH2 selective inhibitor without abnormal clinical signs at once daily dose in an EZH2 GOF mutant lymphoma cell xenograft mice model as well as in a bladder cancer cell xenograft mice model harboring a genetically mutated regulatory SWI/SNF complex protein (e.g. ARID1A). Taken together, the present studies demonstrated that HM97662 is a novel and potent EZH1/2 dual inhibitor and has the promising potential for the treatment of patients with several types of cancers. Clinical trials to prove the effectiveness of HM97662 identified in preclinical studies need to be carried out immediately. Citation Format: Seung Hyun Jung, DongJin Hong, Jiyoung Hwang, Somin Park, Jooyun Byun, Miyoung Lee, Kyounghwa Koo, Gunwoo Lee, Yu-Yon Kim, Yesol Bak, Young Gil Ahn, YoungHoon Kim, Kwee Hyun Suh. A novel and potent EZH1/2 dual inhibitor, HM97662, demonstrates antitumor activity in malignant tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1142.