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Abstract

PMID

Authors

Na Yang; Jia Hu; Tingwen Li; Juntao Yu; Dongxia Shi; Min Cheng; Zeyu Zhong; Jian Wang; Yang Sai; Weiguo Qing; Guangxiu Dai; Yongxin Ren; Michael Shi; Weiguo Su

Title

Abstract 543: Preclinical characteristic of HMPL-306, a CNS-penetrable dual inhibitor of mutant IDH1 and IDH2

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancer Research	83	7_Supplement	April 04 2023	543	Cancer Res

URL

https://aacrjournals.org/cancerres/article/83/7_Supplement/543/719628

Abstract Text

Background: Mutations in isocitrate dehydrogenase (IDH) 1/2 are frequently identified in various cancers, such as AML, cholangiocarcinoma, chondrosarcoma and glioma. Mutant IDHs (mIDHs) cause accumulated 2-HG, leading to blockage of cell differentiation, thereby inducing malignant transformation. Rare cases were identified carrying co-existing mutations in IDH1 and IDH2. mIDH isoform switching, from mutant IDH1 to mutant IDH2 and vice versa, have been reported as a mechanism of acquired resistance to IDH inhibition in AML and cholangiocarcinoma. Thus, simultaneous inhibition on both mIDH1 and mIDH2 may be a promising strategy to overcome resistance and improve clinical efficacy. HMPL-306, a dual inhibitor of mIDH1/mIDH2, developed by HUTCHMED, is being evaluated in clinical trials. Methods: The inhibition of HMPL-306 on IDH enzymes, including mutant and wild type, was determined by fluorescence-based assay. The selectivity of HMPL-306 was evaluated in 322 kinases (SelectScreenTM) and 88 proteins (Cerep). For cellular activities of HMPL-306, 2-HG production and differentiation were detected in cells harboring mIDH. Human tumor xenograft models carrying IDH1 or 2 mutations were established for evaluating mIDH inhibition by detecting 2-HG in plasma and tumor, and anti-tumor efficacies. Results: HMPL-306 inhibited mutant IDH enzyme activities including IDH1R132H, IDH2R140Q and IDH2R172K, while showed weaker inhibition on IDH1/2 wild type enzymes. HMPL-306 had a superior selectivity profile in a kinase panel and a safety panel, while enasidenib, an approved mIDH2 inhibitor, inhibited Adenosine-A3 with IC50 of 12 nM. In cellular assays, HMPL-306 displayed comparable activities to enasidenib and ivosidenib (approved mIDH1 inhibitor) and suppressed 2-HG through inhibition of mIDH1 or mIDH2 at similar level, indicating an equal potency against mIDH1 and 2. Moreover, in both mIDH1/2 cells, HMPL-306 reduced the levels of histone methylation, and promoted hemoglobin γ and Kruppel1 gene expression, which led to differentiation from immature malignant cells to mature normal cells. Oral administration of HMPL-306 remarkably decreased 2-HG level in plasma and tumor tissues in xenograft models carrying mIDH1 or mIDH2 and the inhibition is more potent and durable than either ivosidenib or enasidenib at the same dose. Pharmacokinetics (PK) study in rodents showed high exposures of HMPL-306 in brain and cerebrospinal fluid, a desirable feature for glioma therapy. Combination treatment of HMPL-306 and azacitidine synergized in releasing the differentiation block in mIDH AML cells. HMPL-306 also significantly improved in vivo anti-tumor efficacy of chemotherapy drugs in solid tumor models with mIDH1/2. Conclusion: HMPL-306 is a potent, dual inhibitor of IDH1/2 mutation. The strong activity and favorable PK profiles support further clinical evaluation.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
IDH2 R140Q	Advanced Solid Tumor	predicted - sensitive	HMPL-306	Preclinical - Biochemical	Actionable	In a preclinical study, HMPL-306 inhibited the enzymatic activity of IDH2 R140Q in a fluorescence-based assay (Cancer Res (2023) 83 (7_Supplement): 543).	detail...
IDH2 R172K	Advanced Solid Tumor	predicted - sensitive	HMPL-306	Preclinical - Biochemical	Actionable	In a preclinical study, HMPL-306 inhibited the enzymatic activity of IDH2 R172K in a fluorescence-based assay (Cancer Res (2023) 83 (7_Supplement): 543).	detail...
IDH1 R132H	Advanced Solid Tumor	predicted - sensitive	HMPL-306	Preclinical - Biochemical	Actionable	In a preclinical study, HMPL-306 inhibited the enzymatic activity of IDH1 R132H in a fluorescence-based assay (Cancer Res (2023) 83 (7_Supplement): 543).	detail...