For research use only. Not for therapeutic Use.
LOXO-195 R-isomer (CAT: I011864) is a potent and selective inhibitor of tropomyosin receptor kinase (TRK). It is specifically designed to target and address potential mechanisms of acquired resistance that may arise in patients receiving larotrectinib (LOXO-101) or multikinase inhibitors with anti-TRK activity. LOXO-195 has shown remarkable efficacy in inhibiting TRK fusions, including acquired resistance mutations, as demonstrated through both enzyme and cellular assays. Notably, its activity against other kinases is minimal, indicating its selectivity for TRK. This compound holds promise as a potential therapeutic option for patients who develop resistance to existing TRK inhibitors or for those with TRK fusion-positive cancers.
| Catalog Number | I011864 |
| CAS Number | 1350884-56-8 |
| Synonyms | LOXO-195; LOXO 195; LOXO195 |
| Molecular Formula | C20 H21 F N6 O |
| Purity | ≥95% |
| Storage | RT |
| Related CAS | 2097002-61-2 |
| Reference | 1. Cancer Discov. 2017 Sep;7(9):934-936. doi: 10.1158/2159-8290.CD-17-0704. Fast-TRKing Drug Development for Rare Molecular Targets. Parikh AR(1), Corcoran RB(2). Author information: (1)Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts. (2)Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts. [email protected]. Comment on Cancer Discov. 2017 Sep;7(9):963-972. Drug development for rare molecular targets in oncology presents unique challenges. In this issue of Cancer Discovery, Drilon and colleagues report the accelerated development and innovative initial clinical trial strategy of a next-generation TRK inhibitor, LOXO-195, designed to overcome common secondary TRK resistance mutations. Cancer Discov; 7(9); 934-6. ©2017 AACR.See related article by Drilon et al., p. 963. 2. Cancer Discov. 2017 Sep;7(9):963-972. doi: 10.1158/2159-8290.CD-17-0507. Epub 2017 Jun 3. A Next-Generation TRK Kinase Inhibitor Overcomes Acquired Resistance to Prior TRK Kinase Inhibition in Patients with TRK Fusion-Positive Solid Tumors. Drilon A(1)(2), Nagasubramanian R(3), Blake JF(4), Ku N(5), Tuch BB(5), Ebata K(5), Smith S(5), Lauriault V(5), Kolakowski GR(4), Brandhuber BJ(4), Larsen PD(4), Bouhana KS(4), Winski SL(4), Hamor R(4), Wu WI(4), Parker A(4), Morales TH(4), Sullivan FX(4), DeWolf WE(4), Wollenberg LA(4), Gordon PR(3), Douglas-Lindsay DN(3), Scaltriti M(6)(7), Benayed R(7), Raj S(7), Hanusch B(1), Schram AM(1), Jonsson P(8), Berger MF(2)(6)(9), Hechtman JF(2)(7), Taylor BS(6)(8)(9), Andrews S(4), Rothenberg SM(10), Hyman DM(11)(2). Author information: (1)Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. (2)Weill Cornell Medical College, New York, New York. (3)Nemours Children/'s Hospital, Orlando, Florida. (4)Array BioPharma, Boulder, Colorado. (5)Loxo Oncology, Inc., Stamford, Connecticut. (6)Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York. (7)Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York. (8)Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York. (9)Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York. (10)Loxo Oncology, Inc., Stamford, Connecticut. [email protected] [email protected]. (11)Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. [email protected] [email protected]. Comment in Cancer Discov. 2017 Sep;7(9):934-936. Larotrectinib, a selective TRK tyrosine kinase inhibitor (TKI), has demonstrated histology-agnostic efficacy in patients with TRK fusion-positive cancers. Although responses to TRK inhibition can be dramatic and durable, duration of response may eventually be limited by acquired resistance. LOXO-195 is a selective TRK TKI designed to overcome acquired resistance mediated by recurrent kinase domain (solvent front and xDFG) mutations identified in multiple patients who have developed resistance to TRK TKIs. Activity against these acquired mutations was confirmed in enzyme and cell-based assays and in vivo tumor models. As clinical proof of concept, the first 2 patients with TRK fusion-positive cancers who developed acquired resistance mutations on larotrectinib were treated with LOXO-195 on a first-in-human basis, utilizing rapid dose titration guided by pharmacokinetic assessments. This approach led to rapid tumor responses and extended the overall duration of disease control achieved with TRK inhibition in both patients.Significance: LOXO-195 abrogated resistance in TRK fusion-positive cancers that acquired kinase domain mutations, a shared liability with all existing TRK TKIs. This establishes a role for sequential treatment by demonstrating continued TRK dependence and validates a paradigm for the accelerated development of next-generation inhibitors against validated oncogenic targets. Cancer Discov; 7(9); 963-72. ©2017 AACR.See related commentary by Parikh and Corcoran, p. 934This article is highlighted in the In This Issue feature, p. 920. |
