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ALK inhibitors: iterative upgrade, targeted therapies strike with precision

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Fourth-generation ALK inhibitors are currently  under investigation. Biomedical technology is constantly advancing and drug  development is constantly evolving. The rapid pace of ALK-targeted drug  development, along with the concurrent knowledge gained about resistance  mechanisms, illustrates the pivotal role of an iterative, systematic discovery  process in advancing oncology research and transforming patients' lives.
Medicilon has established a one-stop  platform for preclinical biopharmaceutical R&D services, including drug  discovery, pharmacological research, and preclinical research. The one-stop  R&D platform strongly integrates advantageous resources, promotes efficient  collaboration across departments, gives full play to the synergistic effect of  1+1>2, and accelerates the development of new drugs.


Lung cancer is one of the leading causes of  cancer deaths worldwide, and it ranks first in terms of incidence and mortality  in China. Lung cancer is classified into non-small cell lung cancer (NSCLC) and  small cell lung cancer (SCLC) according to its biological characteristics,  treatment, and prognosis. In China, NSCLC accounts for 80-85% of patients, and  about 3%-7% of NSCLC patients have ALK gene mutations. Brain metastases occur  in 20-40% of ALK-positive advanced NSCLC patients at the time of initial  diagnosis, and the incidence increases with time.
 ALK is found in anaplastic large cell  lymphoma (ALCL). Given the close relationship between ALK mutations and tumors,  many researchers have developed a series of anti-tumor drugs that mainly target  ALK. ALK is a tyrosine kinase closely related to tumors, and the ALK gene is  found in a range of malignancies, including NSCLC, mesenchymal large cell  lymphoma, and neuroblastoma, with rearrangements, point mutations, or  amplifications. Because of their rarity and precision, ALK fusion mutations are  known as "diamond mutations".
 As the number of therapeutic agents for  ALK-positive patients increases, it is crucial to achieving precise treatment,  and there is a general clinical consensus that the foundation of precise  treatment is precise diagnosis. Currently, several precise diagnostic methods  are available to detect the expression of ALK fusion genes in tumor tissues,  which is revolutionary for the molecular diagnosis of NSCLC in recent years.

ALK structure & mechanism of action

ALK (mesenchymal lymphoma kinase): also  known as ALK tyrosine kinase receptor or CD246, is synthesized by the ALK gene  encoding it. ALK is a receptor tyrosine kinase that belongs to the insulin  receptor superfamily and is highly homologous to leukocyte tyrosine kinase  (LTK). The human ALK gene is located on chromosome segment 2p23 and encodes a  1620 amino acid polypeptide that is post-translationally modified to produce a  mature ALK protein of approximately 200-220 kDa. ALK maturation protein is a  classical receptor tyrosine kinase that includes an extracellular ligand  binding structural domain, a transmembrane structural domain, and an  intracellular tyrosine kinase structural domain. The kinase structural domain  shares a 3-tyrosine motif (Tyr1278, Tyr1282, and Tyr1283) with other kinases of  the same family, which is located in the activation loop and represents the  major autophosphorylation site for kinase activity. ALK is activated only upon  ligand-induced homodimerization and is inactivated in the absence of ligand by  dephosphorylation of the receptor protein tyrosine phosphatase β and zeta  complex (PTPRB/PTPRZ1).

 ALK protein structure.jpg  ALK protein structure [1]

ALK activates multiple pathways, including  phospholipase C γ (PLCγ), JAK-STAT, PI3K-AKT, mTOR, sonic hedgehog, JUNB, CRKL-C3G  (also known as RAPGEF1)-RAP1 GTPase and MAPK signaling cascades, affecting cell  growth, transformation, and anti-apoptotic signaling. ALK is activated only  upon ligand-induced homodimerization and is inactivated in the absence of  ligand by dephosphorylation of the receptor protein tyrosine phosphatase β and  zeta complex (PTPRB/PTPRZ1).

ALK signaling pathway.jpg  ALK signaling pathway [1]

Iterative history of ALK inhibitor  development

In 2011, Crizotinib was approved by the FDA  for the treatment of advanced ALK-positive NSCLC, only 4 years after Soda et  al. identified ALK rearrangement as a potential oncogenic driver in NSCLC.  Crizotinib is an oral, small-molecule ATP-competitive ALK inhibitor that was  initially used as a MET TKI and then rapidly switched to target ALK after the  discovery of the role of ALK rearrangement in NSCLC. Thus began the continuous  iterative development of ALK inhibitors.

 History of ALK inhibitor development in  NSCLC.png  History of ALK inhibitor development in  NSCLC [2]

First-generation ALK inhibitors

 The first FDA-approved ALK-TKI drug,  approved by the FDA in August 2011, filled the gap of targeted drugs in  ALK-positive NSCLC at that time. Crizotinib is an effective oral tyrosine  kinase inhibitor for ALK fusion genes or locally advanced or metastatic ROS1  fusion-positive NSCLC. Crizotinib is more effective than chemotherapy and has  fewer toxic side effects.

Second-generation ALK inhibitors

 Approved by the FDA in December 2015 for  the treatment of locally advanced or metastatic ALK-positive NSCLC whose  disease has progressed or failed after treatment with Crizotinib. Alectinib is  a potent and selective ALK inhibitor with good efficacy in patients with  Crizotinib-refractory ALK-positive NSCLC with CNS metastasis. It has good  brain-entry properties.
 Approved by the FDA in May 2017 for the  treatment of ALK-positive metastatic NSCLC. Indicated in ALK-positive,  ROS1-positive locally advanced or metastatic NSCLC. Doubling of  progression-free survival and significant efficacy in brain metastases.
 Approved for marketing by NMPA in November  2020. The first new domestic class 1 drug for the treatment of ALK-mutated  advanced NSCLC, providing a new treatment option for NSCLC patients. It is  indicated for ALK-positive locally advanced or metastatic NSCLC with high  selectivity. For ALK-positive locally advanced or metastatic NSCLC that has  progressed after prior treatment with Crizotinib or is intolerant to  Crizotinib. It compares favorably with similar imported drugs in terms of  efficacy, has a higher response rate, especially in patients with brain  metastases, and has a good and controlled safety profile.
 Approved by the FDA in April 2017 for the  treatment of ALK-positive NSCLC that is intolerant after treatment with  Crizotinib. Targeted inhibition of both ALK and EGFR. Brigatinib is an orally  effective selective ALK and ROS1 tyrosine kinase inhibitor. Brigatinib has  better overall and intracranial efficacy compared to Crizotinib in patients  with ALK-positive NSCLC treated with primary ALK inhibitors. Brigatinib was  well tolerated for long-term use.

Third-generation ALK inhibitors

 Approved for marketing by the FDA  in  November 2018 for the treatment of patients with ALK-positive NSCLC whose  disease continues to progress, who have received Crizotinib and at least one  other ALK inhibitor for metastatic disease, or whose disease progresses to  metastatic disease after treatment with Alectinib or Ceritinib. More brain  entry than Alectinib. Lorlatinib has excellent blood-brain barrier penetration,  and the treatment of patients without brain metastases is effective in  preventing brain metastases from occurring. Lorlatinib has a unique chemical  structure with a large cyclic amide structure, which is more penetrating and  binding to ALK, and therefore shows better results in clinical practice.

Quadruple-generation ALK inhibitors

Double mutation-active ALK TKI
 Quad-generation ALK TKI is being developed  to overcome ALK mutations, mainly due to the sequential use of  "mono-mutation-active" ALK TKI, including in particular the ALK  G1202R-based double mutation. Four generations of ALK TKI are currently in  development, including TPX-0131 and NVL-655. In addition to broad-spectrum  single ALK mutations, TPX-0131 and NVL-655 also inhibit acquired double  "compound" ALK mutations. TPX-0131 and NVL-655 can overcome multiple  double mutations in vitro.

Inhibitory activity of TPX-0131 and NVL-655.png  Inhibitory activity of TPX-0131 and NVL-655  [3]

TPX-0131 is a potent CNS-permeable  macrocyclic molecule that inhibits ALK fusion proteins. In cellular assays,  TPX-0131 was more effective than the five currently approved ALK inhibitors  against WT ALK and many types of ALK-resistant mutations (e.g., G1202R, L1196M,  and compound mutations). In biochemical assays, TPX-0131 effectively inhibited  WT ALK and 26 ALK mutants (single and compound mutations) with an IC50<10  nM. TPX-0131 acted on ALK (G1202R) and ALK compound mutation-dependent  xenograft tumor models, leading to complete tumor regression. After oral  administration of TPX-0131 to rats, TPX-0131 levels in the brain were observed  to be approximately 66% of those in plasma.

Structural design of TPX-0131.png Structural design of TPX-0131 [4]

Medicilon helps ALK inhibitor development

Project example: ALK degradation agent  SIAIS164018

SIAIS164018 is an orally effective  degradation agent that degrades not only ALK or mutant EGFR but also other  tumor proteins involved in metastasis. Particularly potent targeting of  L858R+T790M mutant EGFR, the two most important targets in non-small cell lung  cancer. SIAIS164018 inhibits cell migration and invasion of Calu-1 and  MDA-MB-231. SIAIS164018 also degrades several important tumor proteins  associated with metastasis, such as FAK, PYK2, and PTK6.

The multi-targeted degradation agent  SIAIS164018.png  The multi-targeted degradation agent  SIAIS164018[5]

In this study, Medicilon’s researchers  evaluated pharmacokinetic (PK) data of SIAIS164018 in rats administered  intravenously and orally The data showed that SIAIS164018 was well bioavailable  and tolerated in vivo.

Pharmacokinetic study of SIAIS164018.png  Pharmacokinetic study of SIAIS164018 [5]

Project example: ALK inhibitor CGT-9475

On July 22, 2022, CGT-9475, a new  generation ALK inhibitor developed by CGeneTech, was approved by FDA to enter  clinical trials. ALK inhibitors have significant advantages in clinical  application, but the use of ALK inhibitors will inevitably generate secondary  drug resistance and brain metastasis problems. CGT-9475 aims to overcome drug  resistance and solve the problem of CNS metastasis with quality and  differentiated development. CGT-9475 showed significant inhibitory effects  against drug-resistant mutations such as L1196M and RET in NSCLC cell lines in  preclinical research. Meanwhile, CGT-9475 demonstrated a good blood-brain barrier  penetration effect in preclinical research, which will bring new hope for NSCLC  brain metastasis patients. Medicilon provided a complete preclinical  development service for CGT-9475 (two years of preclinical candidate screening,  followed by systematic pharmacological studies, pharmacodynamic studies,  pharmacokinetic studies, safety evaluation studies, and IND filing). CGT-9475  is expected to be used for follow-up treatment after resistance to existing ALK  inhibitors.

Project case: 4th generation ALK inhibitor  innovation drug development

Lorlatinib, as a 3rd generation ALK  inhibitor, has shown excellent clinical efficacy but also faces the problem of  treatment resistance, in which compound mutations are an important cause of  resistance. The 4th generation, represented by TPX-0131 and NVL-655, can  effectively inhibit compound mutations, especially NVL-655, which significantly  improves the off-target effect on TRKB and is expected to solve the  neurotoxicity problem of existing drugs. Medicilon has used representative 3rd  generation ALK inhibitors such as TPX-0131 and NVL-655 as positive references  to design and synthesize highly active 4th generation ALK target small  molecules with certain novelty, and to investigate and study them in depth.

Summary and outlook

In recent years, with the implementation  and expansion of China's "major new drug creation" science and  technology major projects, China's local pharmaceutical R&D innovation  capacity has greatly improved, which has injected a strong impetus into the global  pharmaceutical R&D field, meaning that more innovative drugs are expected  to be accelerated to market. In the direction of drug development, more and  more pharmaceutical R&D workers are devoting themselves to targeted drug  development to meet more patients' needs and keep gathering efforts to achieve  breakthroughs!
 [1] Carminia Maria Della Corte, et al. Role  and targeting of anaplastic lymphoma kinase in cancer. Mol Cancer. 2018 Feb  19;17(1):30.
 [2] Brandon Golding, et al. The function  and therapeutic targeting of anaplastic lymphoma kinase (ALK) in non-small cell  lung cancer (NSCLC). Mol Cancer. 2018 Feb 19;17(1):52.
 [3] Sai-Hong Ignatius Ou, et al. Will the  clinical development of 4th-generation "double mutant active" ALK  TKIs (TPX-0131 and NVL-655) change the future treatment paradigm of ALK+ NSCLC?  Transl Oncol. 2021 Nov;14(11):101191. doi: 10.1016/j.tranon.2021.101191.
 [4] Brion W Murray, et al. TPX-0131, a  Potent CNS-penetrant, Next-generation Inhibitor of Wild-type ALK and  ALK-resistant Mutations. Mol Cancer Ther. 2021 Sep;20(9):1499-1507. doi:

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