Asahi Kasei Pharma is one of the healthcare subsidiaries of Asahi Kasei Group. Many of the pharmaceutical products of Asahi Kasei Pharma are unique partly due to Asahi Kasei Pharma’s origins in chemicals and fermentation rather than traditional pharmaceuticals. While we are a fully integrated pharmaceutical company with R&D from discovery through clinical development, we have experienced a few setbacks in research in recent years, leaving us with few original development programs. To enhance the productivity of our research programs, we are now pursuing an open innovation strategy and focusing on our advantages in communication between scientists derived from the scale of our laboratories and our access to scientists from the non-pharmaceutical businesses under our conglomerate, the Asahi Kasei Group.

Max Planck Institute of Psychiatry was founded by Emil Kraepelin in 1917 with a unique setting focusing only on basic research of psychiatry, and now has been established for basic and clinical research of mood disorders, especially depression. Since depression is a complex disease, we believe that personalized medication must be taken into account based on diagnostic markers. We began in late 1990’s Munich Antidepressant Response Signature (MARS) project in order to enhance the therapeutic effects according to sub-population of patients by genetic variants or stress hormone responses. This article provides an example of our translational approach focusing FKBP5 found in association with antidepressant responses and relapse from MARS cohorts. Further, our long-term challenges to validate efficacies of CRH antagonists on mood and sleep disorders will be mentioned. Translational psychiatry is requisite and must proceed for curing all individuals suffering from mental diseases.

Alzheimer’s disease (AD) is a neurodegenerative process involving amyloid-β (Aβ) peptide deposition and progressive memory loss. As a candidate retinoid drug for AD, retinoic acid receptor (RAR) agonist Am80 (0.5mg/kg/day, for 14 weeks) was administrated and reduced levels of insoluble Aβ₄₂ (about 15% reduction) in brains of 5-month-old APP23 mice, an AD model. But the treatment did not give behavioral improvements detectable. In contrast, co-administration for 17days, of Am80 (0.5mg/kg/day) with a specific retinoid X receptor (RXR) agonist HX630 (5mg/kg/day), which strongly enhances the biological effects of RARs in the presence of RAR agonist, resulted in a highly significant improvement in the behavioral test concomitantly with a decrease of insoluble Aβ₄₂ peptides (about 50% reduction) in 8.5-month-old APP23 mice. Combination treatment with RAR and RXR agonists may be an effective approach for AD therapy.

Renal sodium-dependent glucose transporter 2 (SGLT2) plays an important role in reabsorption of filtered glucose in proximal tubule and therefore be an attractive target for type 2 diabetes treatment. We have given considerable attention to 5-thioglucose derivative as an SGLT2 inhibitor. After the optimization of the selective inhibition activity and the pharmacokinetics, we found C-thioglucoside derivative/luseogliflozin exhibits a good glucose lowering effect, and promising pharmacokinetic profiles as a drug candidate. In Phase II study, HbA1c decreased significantly at the end of treatment in the 1, 2.5, 5 and 10mg luseogliflozin groups compared with placebo (－0.29, －0.39, －0.46, and －0.43%, resp., vs. +0.22%; all P<0.001). Luseogliflozin was well tolerated, improved glycemic control over 12 week of treatment at all tested doses.

ALK has recently emerged as an attractive target for cancer therapy, since identification of a novel oncogenic fusion gene, EML4-ALK in 2007. Intensive structural optimization of a unique tetracyclic screening hit from Chugai’s corporate library led to discovery of alectinib. Alectinib is a potent and selective ALK inhibitor and is highly efficacious against mouse models with EML4-ALK positive tumor. Alectinib showed good efficacy and tolerability in a Japanese Phase I/II clinical study and based on the result, it was approved for the treatment of ALK fusion gene-positive unresectable NSCLC patients in July 2014.

Kinesin spindle protein (KSP) plays an important role in the early stages of mitosis. A large number of KSP inhibitors have been reported and some of them entered into clinical trials. We previously identified S-trityl-_L-cysteine (STLC) as a selective KSP inhibitor from our HTS campaign and reported that several STLC derivatives induced M-phase accumulation and subsequent apoptosis in cells. Here, we report further optimizations using docking modeling in the L5 allosteric binding site, which led to the discovery of novel cysteine derivatives with two fused phenyl ring in the trityl group giving low nanomolar range KSP ATPase inhibition. The representative derivatives potently inhibited cell growth of HCT116 cells and significantly suppressed tumor growth in the xenograft model. Thus, the novel cysteine derivatives could be new lead compounds in the design of clinical candidates for next-generation KSP inhibitors as antitumor chemotherapies.

Bombesin receptor subtype-3 (BRS-3), known as a promising target for anti-obesity, is expressed not only in the brain but also in the intestine. Merck’s clinical candidate, which showed anti-obesity effects in rats and dogs also caused cardiovascular (CV) adverse effects, such as an increase of body temperature, heart rate and blood pressure in animals. Hence, lowering the exposure of the compound to the brain is expected to avoid CV effects. We designed a novel bicyclic diazepine from a structural similarity between our HTS compounds and Merck’s candidate, and reduced brain penetration by lowering lipophilicity. To identify potent compounds without any CV effects on the central nerve system, a labile carboxylic ester with an antedrug functionality was introduced. Consequently, an antedrug, 11c, showed significant in vivo efficacy and no clear CV effect in dog iv infusion. Our study has paved the way for development of anti-obesity drugs with a safer profile.

Both antisense oligonucleotides and aptamers that suppress mRNA expression and inhibit protein function are in market in US as Nucleic acids therapeutics (NAT). Furthermore, many candidates are in clinical trials. NAT are paid attention as novel modality because NAT can address molecules that have been undruggable with conventional therapeutics such as antibodies and small molecules. In this review, I describe properties of chemical modification for oligonucleotides and the NAT business with their oligonucleotides.