Inhibition of c-Jun N-terminal kinase signaling increased apoptosis and prevented the emergence of ALK-TKI-tolerant cells in ALK-rearranged non-small cell lung cancer

Anaplastic lymphoma kinase-tyrosine kinase inhibitors (ALK-TKIs) have improved clinical outcomes in non-small cell lung cancer (NSCLC) harboring ALK- rearrangements. However, a small population of tumor cells survives due to adaptive resistance under drug pressure and ultimately acquires drug resistance. Thus, it is necessary to elucidate the mechanisms underlying the prevention of drug resistance to improve the prognosis of patients with ALK-rearranged NSCLC. We identified novel adaptive resistance, generated through c-Jun N-terminal kinase (JNK)/c-Jun signaling, to initial ALK-TKIs—alectinib and brigatinib—in ALK-rearranged NSCLC. Inhibition of JNK/c-Jun axis showed suppression of growth and promotion of apoptosis induced by ALK-TKIs in drug-tolerant cells. JNK inhibition, in combination with the use of ALK-TKIs, increased cell apoptosis through repression of the Bcl-xL proteins, compared with ALK-TKI monotherapy. Importantly, combination therapy targeting JNK and ALK significantly d..... READ ARTICLE

Cancer Letters DOI:10.1016/j.canlet.2021.09.018

Authors: Keiko Tanimura, Tadaaki Yamada, Mano Horinaka, Yuki Katayama, Sarina Fukui, Kenji Morimoto, Takayuki Nakano, Shinsaku Tokuda, Yoshie Morimoto, Masahiro Iwasaku, Yoshiko Kaneko, Junji Uchino, Kazue Yoneda, SeijiYano, ToshiyukiSakai and KoichiTakayama

Precision therapy with anaplastic lymphoma kinase inhibitor ceritinib in ALK-rearranged anaplastic large cell lymphoma

This ceritinib translational study in NPM1-ALK+ ALCL provides a strong rationale for a prospective study of ceritinib in ALK+ T-cell lymphomas and other ALK+ hematologic malignancies. READ ARTICLE

ESMO Open DOI: 10.1016/j.esmoop.2021.100172

Authors: V. Subbiah, S. Kuravi, S. Ganguly, D.R. Welch, C.J. Vivian, M.U. Mushtaq, A. Hegde, S. Iyer, A. Behrang, S.M. Ali, R.W. Madison, J.M. Venstrom, R.A. Jensen, J.P. McGuirk, H.M. Amin and R. Balusu

Enteral lorlatinib after alectinib as a treatment option in anaplastic lymphoma kinase‐positive non‐small cell lung cancer with triple problems

Alectinib treatment is effective in patients with anaplastic lymphoma kinase (ALK) gene rearrangement‐positive non‐small cell lung cancer (NSCLC; hereafter ALK‐positive NSCLC) who exhibit central nervous system (CNS) relapse and poor performance status (PS). Lorlatinib treatment is effective upon failure of other ALK inhibitor‐based treatments. However, much remains unknown about the efficacy of lorlatinib in patients with ALK‐positive NSCLC, who have triple problems, carcinomatous meningitis, poor PS, and dysphagia, after alectinib treatment. Here, we report the remarkable response of a 73‐year‐old patient with ALK‐positive NSCLC showing carcinomatous meningitis due to CNS metastases, poor PS, and dysphagia to lorlatinib. Lorlatinib administration through a nasogastric tube alleviated complications related to consciousness within three days, and the patient survived for 16 months after CNS relapse. Lorlatinib could be a treatment option for patients with ALK‐positive NSCLC showing carcinomatous meningitis, poor PS, and dysphagia upon failure of other ALK inhibitor‐based treatments. READ ARTICLE

Respiratory Case Reports DOI:10.1002/rcr2.796

Authors: Kota Sasaki, Yusuke Yokota, Toshihito Isojima, Mayumi Fujii, Kengo Hasui, Yu Chen, Kensuke Saito, Takenori Takahata, Seiko Kindaichi, and Atsushi Sato

EML4-ALK fusion variant.3 and co-occurrent PIK3CA E542K mutation exhibiting primary resistance to three generations of ALK inhibitors

The ALK inhibitors are promising therapeutic agents against lung cancer harboring ALK fusion genes and are currently under development up to the third generation. However, its therapeutic effects are reported to be affected by differences in ALK variants and co-occurrent mutations. Materials and Methods; We experienced an autopsy case of an ALK-positive lung cancer patient who showed primary resistance to three generations of ALK inhibitors. The poor survival time of the case was 14 months. To reveal the mechanism of primary resistance to three generations of ALK inhibitors, we performed next generation sequencing for 12 specimes obtained from an autopsy with covering whole exons of 53 significantly mutated, lung cancer-associated genes and amplicon-based target RNA sequenceing for the ALK fusion gene. The NGS analysis revealed a rare variant.3 of ALK fusion, in which 30 bp of base was inserted at the end of ALK intron.19 and was associated with EML exon.6 [E6_ins30A20] and a co-occurrent oncogenic PIK3CA E542K mutation in all specimens. Structural analysis of the fusion protein ALK [E6_ins30A20] showed no interferance with the binding of ALK inhibitors to the kinase domain. The NGS analysis of primary and metastatic lesions obtained from an autopsy revealed a co-occurrent oncogenic PIK3CA E542K mutation in all specimens. The constitutive activation of PI3K-Akt signal by PIK3CA E542K mutation occurred downstream of ALK signaling pathway, could lead to primary resistance to ALK inhibitors in all generations. READ ARTICLE

Cancer Genetics DOI: 10.1016/j.cancergen.2021.05.010

Authors: Kei Kunimasa, Yosuke Hirotsu, Yoji Kukita, Yumi Ueda, Yoshiharu Sato, Madoka Kimura, Tomoyuki Otsuka, Yuichiro Hamamoto, Motohiro Tamiya, Takako Inoue, Takahisa Kawamura, Kazumi Nishino, Kenji Amemiya, Taichiro Goto, Hitoshi Mochizuki, Keiichiro Honma, Masao Omata and Toru Kumagai

The efficacy of lorlatinib in a lung adenocarcinoma patient with a novel ALK G1202L mutation: a case report

Report reveals the efficacy of lorlatinib in targeting ALK G1202L and can serve as an option for the clinical management of patients with ALK-rearranged lung adenocarcinoma after acquiring G1202L-mediated resistance from prior ALK inhibitor therapy. Furthermore, it demonstrates the sequential use of crizotinib, brigatinib, and lorlatinib in a patient with advanced ALK-rearranged lung adenocarcinoma with an overall progression-free survival of 33.3 months for the sequential ALK inhibitor regimens. His overall survival was 41.5 months inclusive of all regimens. READ ARTICLE

Cancer Biology & Therapy DOI: 10.1080/15384047.2020.1836947

Authors: Zhaoting Meng, Ting Li, Pei Wang, Analyn Lizaso, Dingzhi Huang

Case StudyKirk SmithDecember 30, 2020TKI Resistance, Lorlatinib, ALK-rearranged NSCLC, ALK G1202L, sequential, ALK inhibitor

The Emerging Therapeutic Landscape of ALK Inhibitors in Non-Small Cell Lung Cancer

Review providing a comprehensive overview of the state-of-the-art targeted therapy options in ALK-positive NSCLCs. Resistance, potential therapeutic strategies to overcome drug resistance, and future perspectives for this subset of patients are critically analyzed and summarized. READ ARTICLE

Pharmaceuticals (Basel) DOI: 10.3390/ph13120474

Authors: Valerio Gristina, Maria La Mantia, Federica Iacono, Antonio Galvano, Antonio Russo, Viviana Bazan

Review PaperKirk SmithDecember 13, 2020ALK inhibitor, NSCLC, TKI, alectinib, brigatinib, ceritinib, crizotinib, ensartinib, lorlatinib

Resistance to anaplastic lymphoma kinase inhibitors: knowing the enemy is half the battle won

The bedrock of resistance to TKI is that, after the diagnosis, we face with a different disease that needs to be re-characterized through tissue or/and liquid biopsies. Understanding molecular pathways driving the resistant phenotype will give us the chance to know what we are dealing with and, rather than choose an empirical approach, will help us to properly define the best targeted treatment for these patients. READ ARTICLE

Translational Lung Cancer Research DOI: 10.21037/tlcr-20-372

Authors: Tabbò F, Reale ML, Bironzo P, Scagliotti GV.

Real-World OutcomesKirk SmithDecember 9, 2020ALK, acquired mutations, ALK inhibitor, clonal evolution, resistance

Pyrroformyl-containing 2,4-diaminopyrimidine derivatives as a new optimization strategy of ALK inhibitors combating mutations

Aiming to identify new optimization strategy effective for ALK-mutations, two series of pyrroformyl-containing 2,4-diaminopyrimidine compounds (11a-o, 12a-o) were designed, synthesized and evaluated for their anti-proliferative activities against three cancer cell lines in vitro by MTT assay. The biological evaluations on cellular assay resulted in discovery of compound 11k, which performed considerable activity with IC50 value of 0.034 μM against H2228 cell. Meanwhile, 11k exhibited outstanding enzymatic inhibitory potency with IC50 values of 1.9 nM and 3.1 nM against ALKWT and ALKL1196M, respectively, surpassing the reference ceritinib (IC50 = 2.4 nM and 7.6 nM). Ultimately, the binding mode of 11k with ALK was established to explore the SARs. Overall, 11k was considered as a promising ALK inhibitor for mutation treatment. READ ARTICLE

Bioorganic & Medicinal Chemistry DOI:10.1016/j.bmc.2020.115715

Authors: Meng Cao, Yuxiang Chen, Tianming Zhao, Shangfei Wei, Ming Guo, Xin Zhai

Abstract 579: Ensartinib (X-396), a novel ALK TKI, in Chinese ALK-positive non-small cell lung cancer: A phase I, dose-escalation and expansion study

Ensartinib (X-396) is a novel ALK inhibitor with high activity against a broad range of crizotinib-resistant ALK mutations (such as G1269A, F1174, C1156Y, and T1151) and CNS metastases. This Phase I study (NCT02959619) determined the maximum tolerated dose (MTD) and recommended Phase II dose (RP2D), investigated the safety and PK, and explored the clinical efficiency for the compound as monotherapy in Chinese ALK+ NSCLC patients.Patients with advanced ALK+ NSCLC were treated with oral ensartinib (150, 200, 225, or 250 mg once daily) using a conventional 3+3 dose escalation design. The dose-escalation evaluated patients in 28-day cycles. In the dose-expansion phase, ensartinib was given at the recommended dose to further explore PK and clinical efficacy. Treatment was continued until disease progression, or unacceptable toxicity. The study finds ensartinib was well tolerated in Chinese ALK-positive NSCLC patients with high antitumor activity. RP2D was established at 225 mg QD. Ensartini..... READ ARTICLE

Cancer Research DOI:10.1158/1538-7445.AM2020-579

Authors: Hongyun Zhao, Yuxiang Ma, Yang Zhang, Shaodong Hong, Wenfeng Fang, Yunpeng Yang, Jianjin Huang, Jing Zhao, Yan Huang, Lieming Ding, Li Mao, Giovanni Selvaggi, Li Zhang

Clinical TrialsKirk SmithAugust 1, 2020Ensartinib, X-396, ALK inhibitor, crizotinib, CNS, Chinese, antitumor activity

Abstract 2997: Longitudinal circulating tumor DNA (ctDNA) analysis predicts response and reveals the resistance mechanisms of ensartinib in ALK+ NSCLC patients (pts) progressed on crizotinib

Consistent with previous reports, ensartinib showed high clinical efficacy. Longitudinal ctDNA analysis
could be a powerful tool in predicting treatment outcomes and revealing resistant mechanisms of
ensartinib. We observed G1269A, G1202R and E1210K as the major resistant mutations to ensartinib. READ ARTICLE

Cancer Research DOI:10.1158/1538-7445.AM2020-2997

Authors: Yunpeng Yang, Jie Huang, Tao Wang, Jianya Zhou, Jing Zheng, Jifeng Feng, Wu Zhuang, Jianhua Chen, Jun Zhao, Wei Zhong, Yanqiu Zhao, Yiping Zhang, Yong Song, Yi Hu, Zhuang Yu, Youling Gong, Yuan Chen, Feng Ye, Shucai Zhang, Lejie Cao, Yun Fan, Gang Wu, Yubiao Guo, Chengzhi Zhou, Kewei Ma, Jian Fang, Weineng Feng, Yunpeng Liu, Zhendong Zheng, Gaofeng Li, Ning Wu, Wei Song, Xiaoqing Liu, Shijun Zhao, Lieming Ding, Li Mao, Giovanni Selvaggi, Larry Zhu, Shanshan Xiao, Li Zhang

Clinical TrialsKirk SmithAugust 1, 2020Ensartinib, X-396, ALK inhibitor, post-crizotinib

BRAF V600E mutation and MET amplification as resistance pathways of the second-generation anaplastic lymphoma kinase (ALK) inhibitor alectinib in lung cancer

Background: Anaplastic lymphoma kinase (ALK) targeted therapies have demonstrated remarkable efficacy in ALK-positive lung adenocarcinomas. However, patients inevitably develop resistance to such therapies. To investigate novel mechanisms of resistance to second generation ALK inhibitors, we characterized and modeled ALK inhibitor resistance of ALK-positive patient-derived xenograft (PDX) models established from advanced-stage lung adenocarcinoma patients who have progressed on one or more ALK inhibitors. Conclusions: Bypass signaling pathway through c-MET and BRAF are independent mechanisms of resistance to alectinib. Individualized intervention against these resistance pathways could be viable therapeutic options in alectinib-refractory lung adenocarcinoma. READ ARTICLE

Lung Cancer DOI:10.1016/j.lungcan.2020.05.018

Authors: Ruoshi Shi, Sebastiao N. Martins Filho, Ming Li, Aline Fares, Jessica Weiss, Nhu-An Pham, Olga Ludkovski, Vibha Raghavan, Quan Li, Deepti Ravi, Michael Cabanero, Nadeem Moghal, Natasha B. Leighl, Penelope Bradbury, Adrian Sacher, Frances A. Shepherd, Kazuhiro Yasufuku, Ming-Sound Tsao, Geoffrey Liu

A User’s Guide to Lorlatinib

Rearrangements of the ALK gene are found in approximately 5% of non-small-cell lung cancer. It is of particular importance to test for this rearrangement in patients with metastatic lung adenocarcinoma because these tumors are highly sensitive to therapy with ALK-targeted inhibitors.

Lorlatinib is a reversible potent third generation tyrosine kinase inhibitor that is highly selective and targets ALK and ROS1. It was developed to target resistant ALK mutants including the most common G1202R. Lorlatinib has excellent central nervous system (CNS) penetration and its efficacy has also been demonstrated even in patients with intracranial metastases after progression on second generation ALK inhibitors. Potential toxicities include neurocognitive effects and hyperlipidemia.

“A User’s Guide to Lorlatinib” reviews the mechanism of action, pharmacology and clinical trial data. Also covering the management of adverse events, this “guide” has been prepared to be a practical reference tool to both clinicians and basic researchers. READ ARTICLE

Critical Reviews in Oncology/Hematology DOI:10.1016/j.critrevonc.2020.102969

Authors: Misako Nagasaka, Yubin Ge, Ammar Sukari, Geetika Kukreja, Sai-Hong IgnatiusOu

Recurrent hyperglycemic hyperosmolar state after re-administration of dose-reduced ceritinib, an anaplastic lymphoma kinase inhibitor

Ceritinib is a second-generation anaplastic lymphoma kinase (ALK) inhibitor with clinical activity in crizotinib-resistant ALK-positive non-small cell lung cancer and in treatment-naïve ALK-positive disease. Hyperglycemia is a known adverse event, but the mechanism by which ceritinib causes hyperglycemia is unknown, and whether ceritinib causes hyperglycemic emergencies is unclear. Here, we report the case of a patient with a hyperglycemic hyperosmolar state (HHS) recurrence after the re-administration of dose-reduced ceritinib. A 78-year-old man with type 2 diabetes diagnosed as having advanced lung adenocarcinoma had been treated with alogliptin (25 mg/day) for the diabetes and with ceritinib for the lung cancer. After 28 days of ceritinib administration, he was admitted to our hospital due to HHS. His blood glucose level improved with insulin therapy after discontinuation of the ceritinib. He then received re-administration with a decreased ceritinib dose while maintaining the insul..... READ ARTICLE

Diabetology International DOI:10.1007/s13340-020-00442-w

Authors: Miyoshi, Y., Ogawa, O., Nishida, A. et al.

$Conclusions: These real-life results confirmed lorlatinib as a major treatment option for patients with advanced refractory ALK or ROS1+ NSCLC$

Conclusions: These real-life results confirmed lorlatinib as a major treatment option for patients with advanced refractory ALK or ROS1+ NSCLC

Background: Efficacy of ALK TKIs in patients (pts) with ALK+ non-small cell lung cancer (NSCLC) varies. We evaluated the impact of EML4-ALK fusion variants and other baseline (BL) molecular and clinical variables on clinical efficacy of brigatinib (BRG) vs crizotinib (CRZ) as first ALK TKI therapy in pts with ALK+ NSCLC in the phase 3 ALTA-1L (NCT02737501) trial... Conclusions: EML4-ALK fusion variant 3 and TP53 mutation were identified as poor prognosis biomarkers in ALK+ NSCLC. BRG demonstrated better efficacy than CRZ as first-line therapy in pts regardless of EML4-ALK fusion variant and TP53 mutation status. These findings may help define areas of greatest unmet need. Clinical trial information: NCT02737501 READ ARTICLE

Journal of Clinical Oncology DOI:10.1200/JCO.2020.38.15_suppl.9517

Authors: D. Ross Camidge, Huifeng Niu, Hye Ryun Kim, James Chih-Hsin Yang, Myung-Ju Ahn, Jacky Yu-Chung Li, Maximilian Hochmair, Angelo Delmonte, Alexander I. Spira, Rosario Garcia Campelo, Fabrice Barlesi, Geoffrey Liu, Marcello Tiseo, Cong Li, Miguel Williams, Hyunjin Shin, Pingkuan Zhang, Sanjay Popat

Sequential ALK inhibitor treatment benefits patient with leptomeningeal metastasis harboring non-EML4-ALK rearrangements detected from cerebrospinal fluid: A case report

A 47-year-old female with ALK-rearranged lung adenocarcinoma developed leptomeningeal metastasis (LM) after progression on first-line crizotinib. Alectinib 300 mg was commenced and the patient achieved clinical and radiographic improvements. After nine months of alectinib 300 mg, she started to experience symptomatic LM. Two concurrent non-EML4-ALK rearrangements, LOC388942-ALK and LINC00211-ALK, were identified from the CSF but not from the plasma samples. With the primary lung lesions remaining stable, the alectinib dose was increased to 600 mg twice daily which alleviated the clinical symptoms of symptomatic LM. After 7.6 months of alectinib 600 mg, the patient again experienced CNS progression. With both CSF and plasma samples revealing no druggable mutations, the alectinib dose was re-escalated to 900 mg twice daily, resulting in clinical benefits lasting for two months. Her therapy was then switched to lorlatinib which controlled the disease for 8.7 months until her demise. The L..... READ ARTICLE

Thoracic Cancer DOI:10.1111/1759-7714.13259

Authors: Zhaona Li, Pupu Li, Bing Yan, Qiongqiong Gao, Xiangli Jiang, Zhongli Zhan, Qingna Yan, Analyn Lizaso, Chun Huang

P114-26 ALK Fusion Variant Detection by Targeted RNA-Seq in TKIs Treated ALK-Positive Lung Adenocarcinoma

We retrospectively characterized fusion variant distribution in a cohort of ALK+ lung adenocarcinomas (ADC) with paired clinical data about treatments and outcomes.Diagnostic tumor tissue from advanced ALK+ (by FISH and/or IHC) ADC diagnosed from 2010 to 2018 and treated with single or multiple ALKis were collected (expanded cohort from Gobbini et al. Lung Cancer, 2017). The OncomineTM Solid Tumor Fusion Transcript Kit on an Ion PGM™ system and the Ion Reporter™ software were used to identify targeted ALK fusion gene products (ThermoFisher).Our analysis suggests that different ALK fusion variant might affect ALKi treatment duration in ALK+ lung ADC READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2019.08.1177

Authors: F. Tabbò, E. Gobbini, L. Muscarella, A. Rigutto, D. Trombetta, A. Bonfitto, D. Galetta, E. Maiello, O. Martelli, M. Tiseo, P. Bordi, V. Scotti, L. Ghilardi, V. Gregorc, C. Sergi, S. Pilotto, A. Del, Conte, F. Cappuzzo, D. Cortinovis, G. Osman, C. Bareggi, M. Di Maio, A. Rossi, G. Rossi, E. Bria, M. Volante, G. Scagliotti, P. Graziano, S. Novello, L. Righi

Conference PaperKirk SmithOctober 1, 2019ALK, ALK inhibitor, Fusion variant

OA0206 The Sequential Therapy of Crizotinib Followed by Alectinib: Real World Data of 840 Patients with NSCLC Harboring ALK-Rearrangement (WJOG9516L)

Previous clinical trials demonstrated that alectinib (ALEC) had a longer time-to-progression than crizotinib (CRZ) in 1st-line settings. Information on long-term overall survival (OS), however, is still limited with a few studies having reported that the sequential strategy of “CRZ followed by other ALK-inhibitor” can provide extended OS. In Japan, ALEC was approved for a 1st-line setting earlier than in other countries.We reviewed the clinical data of ALK-rearranged NSCLC patients who received CRZ or ALEC between May 2012 and Dec 2016. Patients were divided into two groups according to the first-administered ALK inhibitor, the CRZ or ALEC group. In order to evaluate the efficacy of the sequential strategy of “CRZ followed by ALEC”, the combined time to treatment failure (TTF) was calculated in the CRZ group as defined by the sum of the “TTF of CRZ” plus the “TTF of ALEC” if patients were treated with ALEC followed by CRZ. In the ALEC group, the “TTF of ALEC” was calculated. The primar..... READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2019.08.415

Authors: S. Watanabe, T. Yamanaka, K. Ito, S. Sakata, H. Daga, T. Kijima, K. Hirano, I. Okamoto, A. Nakamura, T. Kozuki, M. Ishihara, K. Azuma, T. Seto, T. Yokoyama, Y. Oya, H. Kobayashi, K. Nishino, Y. Hattori, K. Nakagawa, N. Yamamoto

Brigatinib in patients with ALK-positive advanced non-small-cell lung cancer pretreated with sequential ALK inhibitors: A multicentric real-world study (BRIGALK study)

Brigatinib is a next-generation ALK inhibitor initially developed in ALK-positive NSCLC pretreated with crizotinib.This retrospective multicentric study analyzed ALK-positive advanced NSCLC patients pretreated with at least one tyrosine-kinase inhibitor, including crizotinib, and enrolled in the brigatinib French early access program. The primary endpoint was investigator-assessed progression-free survival (PFS).Real-world results confirm that the efficacy of brigatinib in a cohort of patients heavily pretreated for ALK-positive advanced NSCLC. READ ARTICLE

Lung Cancer DOI:10.1016/j.lungcan.2019.08.010

Authors: Renaud Descourt, Maurice Perol, Gaëlle Rousseau-Bussac, David Planchard, Bertrand Mennecier, Marie Wislez Alexis Cortot, Florian Guisier, Loïck Galland, Pascal Dô, Roland Schott, Eric Dansin, Jennifer Arrondeau, Jean-Bernard Auliac, Christos Chouaid

Evaluation of drug-induced lung injury by ALK inhibitor: a single center retrospective analysis

Background: Although lung cancer with ALK or ROS-1 gene fusion is rare, antitumor effect by ALK inhibitor can be highly expected. However, details of drug-induced lung injury (DILI), which can be serious side effect, remain unclear. Conclusion: Elderly people and lower renal function may require caution of DILI caused by ALK inhibitor. Images findings were subjected to OP pattern. The clinical course was not probably critical. READ ARTICLE

European Respiratory Journal DOI:10.1183/13993003.congress-2019.PA4734

Authors: Ken Koshikawa, Jiro Terada, Mitsuhiro Abe, Shunichiro Iwasawa, Masashi Sakayori, Kenji Tsushima, Koichiro Tatsumi

Case StudyKirk SmithJuly 11, 2019Drug-induced lung injury, ALK inhibitor, Pneumonia

Improved Manufacturing Route and Polymorphic Control of a Potent and Selective Anaplastic Lymphoma Kinase (ALK) Inhibitor ASP3026

Our effort toward the process improvement of anaplastic lymphoma kinase (ALK) inhibitor ASP3026 (1) is described. A cost-effective and practical synthesis of 1 was accomplished as a result of the change of starting material from 2,4-dichloro-1,3,5-triazine (6) to cyanuric chloride (9) and late-stage introduction of a highly reactive N-methyl piperazine moiety by reductive amination of intermediate ketone 13. The modified process avoided the challenges with the original synthesis and furnished the several hundred kilograms of high-quality API with high economic efficiency, operability, and reproducibility. Furthermore, a sequence of investigation of polymorphic control in the second-generation synthetic route to obtain the thermodynamically desired, most stable polymorph Form A04 is also discussed. READ ARTICLE

Organic Process Research & Development DOI:10.1021/acs.oprd.8b00427

Authors: Yuji Takahama, Kazuyoshi Obitsu, Kazuhiro Takeguchi, Shun Hirasawa, Koji Kobayashi, Takahiro Akiba, Norihiro Ueda, Ryoki Orii, Atsushi Ohigashi, Takumi Takahashi, Minoru Okada, Shigeru Ieda

EditorialKirk SmithJuly 11, 2019ALK inhibitor, SNAr reaction, 1, 3, 5-triazine, polymorph