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The L858R activating mutation in Epidermal Growth Factor Receptor (EGFR) accounts for approximately 40% of EGFR-mutant non-small cell lung cancer (NSCLC). These patients receive targeted therapy targeting EGFR mutation. To date all approved EGFR tyrosine kinase inhibitors (TKIs) are ATP competitive inhibitors, inevitably lead to drug resistance and to disease progress. Osimertinib is a third-generation EGFR TKI that selectively inhibits both EGFR TKI-sensitizing (L858R) mutation and T790M mutation that confers acquired resistance to first- and second-generation EGFR-TKIs. The patients develop secondary resistance L858R/C797S and L858R/T790M/C797S to this treatment in some cases. There have been strong unmet needs for specific therapies targeting C797S resistance mutations. Additionally, toxicities caused by inhibition of wild-type (WT) EGFR are frequently reported with the first-generation inhibitors (e.g. Gefitinib and Erlotinib). Our Compound A is a highly mutant-selective fourth-generation allosteric inhibitor that targets L858 activating mutations and without affecting EGFR WT that compares favorably with all ATP competitive inhibitors, indicating that it might avoid potential toxicities from targeting EGFR WT. Compound A has a single-digit nanomolar potency against L858R activating mutation and those harboring T790M and C797S resistance mutations. Oral administration of Compound A to tumor-bearing mice showed significant antitumor activity as a single-agent at well-tolerated doses via inhibiting EGFR pathway in the engineered osimertinib-resistance EGFRL858R/T790M/C797S and EGFRL858R/C797S CDX models. Furthermore, Compound A demonstrated excellent efficacy in EGFRL858R/T790M CDX model as a single-agent. Collectively, Compound A has a robust potency against L858R activating mutations including T790M, C797S, and T790M/C797S that cause acquired resistance to ATP competitive EGFR TKIs in vitro and in vivo. Based on the preclinical data, Compound A is a potent, orally available, and mutant-selective fourth-generation allosteric inhibitor of EGFR with L858R activating mutations for the treatment of NSCLC, suggesting that it might have the potential to demonstrate activity in the first line and resistance settings as a single agent. The pre-clinical data described here supports the clinical development of Compound A in NSCLC patients with L858R activating mutations of EGFR. Citation Format: Yeji Byeon, Seung Hee Jung, Daseul Yoon, Seock Yong Kang, Jiyeon Park, Hyeim Jo, Seong-Il Choi, Somyi Park, Seung-chul Lee, Yang Hun Tae, Tae Min Kim, Sung-Yup Cho, Soyeon Kim, Donghyun Ko, Dong-Kyu Kim, Dong-Wan Kim. Compound A, a fourth-generation allosteric inhibitor, a potent and highly selective EGFR with L858R activating and C797S resistance mutations for the treatment of NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5477.

Previous work has revealed that progerin-lamin A binding inhibitor (JH4) can ameliorate pathological features of Hutchinson-Gilford progeria syndrome (HGPS) such as nuclear deformation, growth suppression in patient’s cells, and very short life span in an in vivo mouse model. Despite its favorable effects, JH4 is rapidly eliminated in in vivo pharmacokinetic (PK) analysis. Thus, we improved its property through chemical modification and obtained an optimized drug candidate, Progerinin (SLC-D011). This chemical can extend the life span of LmnaG609G/G609G mouse for about 10 weeks and increase its body weight. Progerinin can also extend the life span of LmnaG609G/+ mouse for about 14 weeks via oral administration, whereas treatment with lonafarnib (farnesyl-transferase inhibitor) can only extend the life span of LmnaG609G/+ mouse for about two weeks. In addition, progerinin can induce histological and physiological improvement in LmnaG609G/+ mouse. These results indicate that progerinin is a strong drug candidate for HGPS., Kang, Park and colleagues develop and demonstrate the effects of a new drug candidate for treatment of Hutchinson-Gilford progeria syndrome pathologies. Progerinin extends the life span of mice used to model this disease and induces histological and physiological improvements.

Previous work has revealed that progerin-lamin A binding inhibitor (JH4) can ameliorate pathological features of Hutchinson-Gilford progeria syndrome (HGPS) such as nuclear deformation, growth suppression in patient's cells, and very short life span in an in vivo mouse model. Despite its favorable effects, JH4 is rapidly eliminated in in vivo pharmacokinetic (PK) analysis. Thus, we improved its property through chemical modification and obtained an optimized drug candidate, Progerinin (SLC-D011). This chemical can extend the life span of Lmna

A new and efficient method for the asymmetric synthesis of 3,4,6-trisubstituted 2,5-diketopiperazines has been developed. The dynamic kinetic resolution of L-amino-acid-derived α-bromo tertiary amides in the nucleophilic substitution reaction with p-anisidine and a subsequent deprotection-cyclization process provides rapid access to diverse cis-2,5-diketopiperazines 5a–5o and proline-containing trans-2,5-diketopiperazines 5p–5t in enantiomerically pure form in 45–67 % overall yields.

Enantiopure N , N -dialkyl-( S )-2-amino-1,1,2-triphenyl­ethanols were prepared using a new synthetic methodology and tested for their ability to catalyze the enantioselective addition of diethylzinc to aldehydes. The structural modification of N-substituents of the catalysts led us to identify N -methyl- N -( S )-1-phenyl­ethyl-substituted 4d as an effective catalyst for the addition. Also disclosed is a kinetic resolution of racemic flavene-3-carbaldehydes with the chiral catalyst.

Pro dipeptide analogues 2 and 3 as shown in Scheme1. The treatment of two diastereomeric mixture (1:1) of N-(α-bromo-α-phenylacetyl)-(L)-proline methyl ester 1 withan amine nucleophile (diphenylmethylamine or dibenzyl-amine) in the presence of tetrabutylammonium iodide (TBAI)and diisopropylethylamine (DIEA) in CH

A new class of modular chiral catalysts derived from various amino acid-L-Pro dipeptides was prepared, and the catalysts were tested for their ability to catalyze the enantioselective addition of dimethylzinc to aromatic aldehydes. Dipeptides derived from L-Asp-L-Pro were identified as effective catalysts for the addition at room temperature with up to 97:3 er and 95 % yield.

Dynamic resolution of α-halo esters derived from five chiral alcohols has been investigated in nucleophilic substitution with ethylenediamine nucleophiles. Stereoselective substitution of α-halo esters and following spontaneous cyclization provide a practical protocol for asymmetric syntheses of 3-substituted piperazin-2-ones up to 94:6 er.

Based on our pharmacophore model of the aryl diketoacids (ADKs), we designed and prepared a series of novel ADK analogues, which showed potent inhibitory activities against the NS5B polymerase in the submicromolar range. Pharmacophore-guided docking study revealed that the antiviral activities of the ADKs are highly dependent upon the aryl linker as well as the size and position of the aromatic substituent. It is of another importance that, unlike previously reported ADKs, three ADK analogues synthesized in this study effectively blocked Hepatitis C Virus (HCV) replication in the replicon systems.

A 3D-CoMFA model with pranlukast analogues was constructed, which could be applied to predict the antagonistic activity of aryl benzyl ether analogues against LTD4. Molecular modeling and 3D-CoMFA studies were performed on 78 pranlukast analogues and 14 aryl benzyl ethers to evaluate the antagonistic behavior of aryl benzyl ethers and provide information for further modification of this kind of compounds. The aryl benzyl ether core was found to be in excellent three dimensional match with the central planar moiety of pranlukast analogues, and the pranlukast 3D-CoMFA model could be successfully applied to predict the biological activity of aryl benzyl ether analogues.

The central role of cyclin-dependent kinases (CDKs) in cell cycle regulation makes them a promising target for studying inhibitory molecules that can modify the degree of cell proliferation. The discovery of specific inhibitors of CDKs such as polyhydroxylated flavones has opened the way to investigation and design of antimitotic compounds. Among the polyhydroxylated flavones, flavopiridol (1, Figure 1) has completed phase I clinical trial where it showed antitumor effect in patients with refractory neoplasms. This encouraging result, which is consistent with the ability of 1 to inhibit proliferation of cancer cells in vitro makes polyhydroxylated flavone an interesting target for further analogue synthesis. In continuation of our studies aimed toward the development of more potent and more selective anticancer agents, we designed flavone derivatives for further biological evaluation. The flavone naringenin is widely spread in nature and easily extracted from a lot of different plants. Their protective effect against lipid peroxidation of membranes, involved in several physiological and pathological disorders, as aging, inflammation, atherosclerosis, ischemia, toxicity of oxygen and chemical substances has been largely reported. Thus, interesting biological activity as well as structural similarity with flavopiridol makes naringenin one of the most interesting candidates for designing novel CDK2 inhibitors. However, derivatives of naringenin have not been studied extensively presumably due to the synthetic difficulties. Particularly, naringenin is awkward to make derivatives due to its low solubility in water as well as in organic solvents. In view of designing naringenin derivatives, the 7-O position of naringenin (2, Figure 1) is particularly attractive because it is well known that electrophiles react with hydroxyl group preferentially at the 7-position. Also, comparison of the biological activity of 7-O-substitued naringenin with that of flavopiridol would provide interesting insights into designing novel flavonoid CDK2 inhibitors due to their subtle distinction in three dimensional structures. On the other hand, as a limiting factor of the use of flavonoids is their low water solubility, another aim of this study was to increase the solubility and dissolution rate of naringenin by conjugate formation with polar substituents. Thus, we set out to prepare various naringenin-amino acid conjugates (2, Figure 1) because amino acids substituted at the 7-O position would serve as an excellent model for our purpose: formation of the amino acid conjugate would benefit naringenin from the various substituent effect as well as increased solubility. Herein we report our efforts to synthesize the title compounds. Recently, two classes of naringenin derivatives, naringenin 7-O-oleic ester and naringenin 7-O-cetyl ether, were prepared for biological evaluation of their anti-atherogenic activity by using the mixed anhydride strategy. However, in our case, due to the epimerization problem at the amino acid αcarbon under the reaction conditions, we decided to use rather mild coupling conditions which was successfully exploited for the preparation of the amino acid esters of 5,7dihydroxy-3-phenoxychromones (3, Figure 2). Thus, a mixture of naringenin (4), N-Boc-L-alanine, and DMAP in anhydrous THF or DMF was treated with EDCI (Scheme 1) and the reaction was monitored by TLC. However, the reaction did not proceed at all presumably due to the solubility problem of the naringenin. After extensive survey of the appropriate solvent system for the coupling reaction, methylene chloride (CH2Cl2) was found to be the solvent of choice: initial slurry of naringenin and NBoc-L-alanine in anhydrous CH2Cl2 became a clear solution as the reaction proceeds, and the reaction was complete in 2

The novel catalysts (I) and (II) are prepared and derivative (Ia) is found to be the most efficient one for the addition of ZnEt2 to aldehydes.

The modular nature of dipeptide catalysts (I) allows for convenient fine-tuning of their catalytic activity in the dimethylzinc addition towards aromatic aldehydes (II).

Stereoselective substitution of auxiliary-bearing α-halo esters with ethylenediamine derivatives and subsequent spontaneous cyclization proceeds with dynamic resolution to afford 3-substituted piperazinones (III) in up to 88% optical purity.

F-3-2-5 (Fig. 1) is a novel apoptosis inducer which was recently isolated from Streptomyces sp., of which potent anticancer activity warrants further preclinical investigation as well as extensive structure-activity relationship study. 1 Thus, there has been an urgent need to devise an efficient synthetic method of F-3-2-5 which has a synthetically challenging trisubstituted α,β-unsaturated ketone moiety as an integral part. Herein, we report an efficient synthesis of the title compound by using Baylis-Hillman reaction as the key step. A synthetic plan for the title compound is shown in Figure 2. The Baylis-Hillman reaction 2a,2b of methyl vinyl ketone