Saturday, April 25, 2015

Alectinib | ALK Inhibitor | NSCLC Therapy | Cancer Treatment

Common name: Alectinib; AF-802; RG-7853; RO-542802; CH-5424802; Alecensa; Alectinib hydrochloride
Trademarks: Alecensa
Molecular Formula: C30H34N4O2
CAS Registry Number: 1256580-46-7
CAS Name: 9-ethyl-6,6-dimethyl-8-(4-morpholin-4-ylpiperidin-1-yl)-11-oxo-5H-benzo[b]carbazole-3-carbonitrile
Molecular Weight: 482.616
InChI: InChI=1S/C30H34N4O2/c1-4-20-16-23-24(17-26(20)34-9-7-21(8-10-34)33-11-13-36-14-12-33)30(2,3)29-27(28(23)35)22-6-5-19(18-31)15-25(22)32-29/h5-6,15-17,21,32H,4,7-14H2,1-3H3
Activity: Protein Kinase Inhibitor; ALK Inhibitor; Anaplastic Lymphoma Kinase Inhibitor; Antineoplastic Drugs; Treatment of Non-small Cell Lung Cancer; NSCLC Therapy
Status: Launched 2014 (Japan)
Originator: Chugai/Roche

Alectinib as Medicine:

Alectinib (RG7853/AF-802/RO5424802/CH5424802) is an oral drug developed for people with non-small cell lung cancer (NSCLC) whose tumours are identified as ALK+. ALK+ NSCLC is often found in younger people, women and those who have a light or non-smoking history. It is almost always found in people with a specific type of NSCLC, adenocarcinoma.

High-throughput screening was utilized to identify a highly selective ALK inhibitor, yielding Alectinib hydrochloride, with an IC50 of 1.9 nM for ALK enzyme activity in cell-free assays. In a competition binding assay, the Alectinib hydrochloride dissociation constant (Kd) for ALK in an ATP-competitive manner was 2.4 nM. Alectinib hydrochloride displayed inhibitory activity for two hot spot-activating mutations in neuroblastoma (F1174L and R1275Q) comparable to that for wild-type ALK. Weak or no inhibition was seen against 24 protein kinases other than ALK, and when profiled against 402 kinases, including mutated kinases, only three (ALK, cyclin-G-associated kinase [GAK] and leuko-cyte tyrosine kinase receptor [LTK]) showed more than 50% inhibition at 10 nM [1].

More importantly, Alectinib also inhibited the ALK gatekeeper mutation L1196M with an IC50 of 1.56 nM. Although the co-crystallization of Alectinib with L1196M mutant was not reported, its structure with wild ALK kinase showed that the C3-cyano moiety has a critical role to interact with the kinase by forming H-bonds and CH/p hydrophobic interactions. In the KARPAS-299 (lymphoma), NB-1 (neuroblastoma) and NCI-H2228 (lung cancer) ALK-positive cell lines, Alectinib inhibited cell proliferation with IC50 values of 3, 4.5 and 53 nM, respectively. It is an ATP-competitive ALK inhibitor, and dose-dependently inhibited EML4-ALK positive NCI-H2228 xenograft model at doses ranging from 2 to 20 mg/kg p.o., q.d. Significant efficacy was also achieved in the EML4-ALK L1196M-driven tumors [2].

Early studies with Alectinib have shown activity on brain metastases, indicating that the drug may be taken up in the brain. The brain is protected by the blood-brain barrier, a network of tightly joined cells that line the inside of the blood vessels in the brain and spinal cord. One of the ways the blood-brain barrier prevents molecules from affecting the brain is to actively eject them from the barrier through a process known as ‘active efflux.’ The active efflux system does not recognise alectinib, which means that it may travel into and throughout brain tissue.

The Global Phase III studies of Alectinib include a companion test co-developed with Ventana Medical Systems, Inc., a member of the Roche Group. Alectinib will be marketed in Japan by Chugai Pharmaceutical, a member of the Roche Group.

The Japanese Ministry of Health, Labor and Welfare (JMHLW) granted Alectinib Orphan Drug designation in 2013, and Chugai filed an NDA with the JMHLW for ALK fusion gene-positive NSCLC. In 2014, Japanese Ministry of Health, Labour and Welfare (JMHLW) approved Alectinib for the treatment of people living with non-small cell lung cancer (NSCLC) that is anaplastic lymphoma kinase fusion gene-positive (ALK+). The approval was based on results from a Japanese Phase I/II clinical study (AF-001JP) for people whose tumours were advanced, recurrent or could not be removed completely through surgery (unresectable).

Alectinib was also granted Breakthrough Therapy Designation (BTD) by the U.S. Food and Drug Administration (FDA) in June 2013 for patients with ALK+ NSCLC who progressed on Crizotinib. BTD is designed to expedite the development and review of medicines intended to treat serious diseases and to help ensure patients have access to them through FDA approval as soon as possible.

Alectinib as Chemical Compound:

Alectinib is a unique second generation ALK inhibitor bearing a 5H-benzo[b]carbazol-11(6H)-one structural scaffold. It originated from Chugai's high throughput screening program and contains a naphtha-[2,3-b]benzofuran-11(6H)-one framework. Replacement of the benzofuran fragment with an indole moiety, followed by optimization of the solvent interaction region as well as adjustment of the E0 region of the ATP binding site to improve the kinase potency, selectivity and the pharmacokinetic properties, led to the compound Alectinib [2].

Other important chemical classifications are:
1. Organocyano compound
2. Organonitrile compound
3. Morphine derivative
4. Piperidine derivative
5. 5H-benzo[b]carbazol-11(6H)-one derivative


Patient reported common adverse events include mainly fatigue (30%), visual disorder (photosensitivity), constipation (gastrointestinal side effects), pulmonary toxicity, rashes, muscular pains (myalgia), peripheral edema, creatine phosphokinase (CPK) elevation, nausea, increased ALT (Alanine transaminase, a check for good liver health). Grade 3 or 4 adverse events such as headaches, neutropenia, fluid retention/peripheral edema, increased gamma-glutamyltransferase, hypophosphatemia are also observed, but their frequency is less. Overall, the profile of Alectinib has been reported to be milder compared to that of Crizotinib [3].

1. Sakamoto, H.; et. al. CH5424802, a selective ALK inhibitor capable of blocking the resistant gatekeeper mutant. Cancer Cell 2011, 19(5), 679-690. 
2. Zhang, A.; et. al. Alectinib: a novel second generation anaplastic lymphoma kinase (ALK) inhibitor for overcoming clinically-acquired resistance. Acta Pharmaceutica Sinica B 2015, 5(1), 34-37.
3. Watanabe, H.; et. al. Response to alectinib after one year of discontinuation of crizotinib in anaplastic lymphoma kinase-positive non-small-cell lung cancer: A case report. Molecular and clinical oncology 2015, 3, 889-891.