Discovery of Inhibitors That Overcome the G1202R Anaplastic Lymphoma Kinase Resistance Mutation

The treatment of patients with advanced non-small-cell lung cancer harboring chromosomal rearrangements of anaplastic lymphoma kinase (ALK) has been revolutionized by the development of crizotinib, a small-molecule inhibitor of ALK, ROS1, and MET. However, resistance to crizotinib inevitably develops through a variety of mechanisms, leading to relapse both systemically and in the central nervous system (CNS). This has motivated the development of “second-generation” ALK inhibitors, including alectinib and ceritinib, that overcome some of the mutations leading to resistance. However, most of the reported ALK inhibitors do not show inhibition of the G1202R mutant, which is one of the most common mutations. Herein, we report the development of a structural analogue of alectinib (JH-VIII-157-02) that is potent against the G1202R mutant as well as a variety of other frequently observed mutants. In addition, JH-VIII-157-02 is capable of penetrating the CNS of mice following oral dosing

Discovery of Inhibitors That Overcome the G1202R Anaplastic Lymphoma Kinase Resistance Mutation

The treatment of patients with advanced non-small-cell lung cancer harboring chromosomal rearrangements of anaplastic lymphoma kinase (ALK) has been revolutionized by the development of crizotinib, a small-molecule inhibitor of ALK, ROS1, and MET. However, resistance to crizotinib inevitably develops through a variety of mechanisms, leading to relapse both systemically and in the central nervous system (CNS). This has motivated the development of “second-generation” ALK inhibitors, including alectinib and ceritinib, that overcome some of the mutations leading to resistance. However, most of the reported ALK inhibitors do not show inhibition of the G1202R mutant, which is one of the most common mutations. Herein, we report the development of a structural analogue of alectinib (JH-VIII-157-02) that is potent against the G1202R mutant as well as a variety of other frequently observed mutants. In addition, JH-VIII-157-02 is capable of penetrating the CNS of mice following oral dosing

Supplementary Figure 1 from Identification of Existing Drugs That Effectively Target <i>NTRK1</i> and <i>ROS1</i> Rearrangements in Lung Cancer

Pathways targeted by the Dana-Farber Targeted Therapy Collection and clinical development status</p

Supplementary figure legends from Identification of Existing Drugs That Effectively Target <i>NTRK1</i> and <i>ROS1</i> Rearrangements in Lung Cancer

Legends to the supplementary figures</p

Supplementary Figure 2 from Identification of Existing Drugs That Effectively Target <i>NTRK1</i> and <i>ROS1</i> Rearrangements in Lung Cancer

Comparison of compound libraries reported in ROS1 kinase screens</p

Supplementary Figure 4 from Identification of Existing Drugs That Effectively Target <i>NTRK1</i> and <i>ROS1</i> Rearrangements in Lung Cancer

Chemical structures of lead compounds</p

Supplementary file 1 from Identification of Existing Drugs That Effectively Target <i>NTRK1</i> and <i>ROS1</i> Rearrangements in Lung Cancer

Contents of the Dana-Farber Targeted Therapy Library and raw data</p

Supplementary Figure 3 from Identification of Existing Drugs That Effectively Target <i>NTRK1</i> and <i>ROS1</i> Rearrangements in Lung Cancer

Inhibition of Ba/F3 CD74-ROS1 proliferation</p

Supplementary Figure 5-7 from Identification of Existing Drugs That Effectively Target <i>NTRK1</i> and <i>ROS1</i> Rearrangements in Lung Cancer

Inhibition of ROS1 signaling in Ba/F3 and UMG-118 cells and the RNPC3-ROS1 fusion</p

Chemically Induced Degradation of Anaplastic Lymphoma Kinase (ALK)

We present the development of the first small molecule degraders that can induce anaplastic lymphoma kinase (ALK) degradation, including in non-small-cell lung cancer (NSCLC), anaplastic large-cell lymphoma (ALCL), and neuroblastoma (NB) cell lines. These degraders were developed through conjugation of known pyrimidine-based ALK inhibitors, TAE684 or LDK378, and the cereblon ligand pomalidomide. We demonstrate that in some cell types degrader potency is compromised by expression of drug transporter ABCB1. In addition, proteomic profiling demonstrated that these compounds also promote the degradation of additional kinases including PTK2 (FAK), Aurora A, FER, and RPS6KA1 (RSK1)