Nonclinical Efficacy and Toxicity and Selection of a Safe Clinical Starting Dose for an NMT Inhibitor in Development for Hematological Malignancies

达沙替尼 癌症研究 林恩 医学 药理学 细胞凋亡 肉豆蔻酰化 毒性 白血病 伊布替尼 淋巴瘤 髓系白血病 原癌基因酪氨酸蛋白激酶Src 生物 内科学 慢性淋巴细胞白血病 受体 磷酸化 生物化学 伊马替尼
作者
Michael J. Weickert,John E. Dillberger,Caren Brown,Francis Phaneuf,John R. Mackey,Randeep Sangha,Luc G. Berthiaume
出处
期刊:Blood [Elsevier BV]
卷期号:136 (Supplement 1): 40-41
标识
DOI:10.1182/blood-2020-141910
摘要

N-myristoylation is the addition of the 14-carbon fatty acid myristate to proteins. This plays a fundamental role in cell signaling: Over 500 proteins are myristoylated, including all 9 Src Family Kinases (SFK) Src, Lyn, Lck, Hck, and Fgr, as well as c-Abl, Gα subunits, caspase truncated (ct-) Bid and ct-PAK2, regulating cell growth and apoptosis. Human myristoylation is performed by two ubiquitously expressed N-myristoyltransferases NMT1 and NMT2. PCLX-001 is a new, orally bioavailable, small-molecule, dual NMT inhibitor under investigation as a novel and selective treatment for B-cell malignancies.In vitro, PCLX-001 inhibits the growth of hematological cancer cells at concentrations 10-fold lower than dasatinib and ibrutinib and prevents SFK recruitment to B cell receptor signaling complex, reducing survival signals and triggering apoptosis. PCLX-001 causes complete tumor regression in NOD/SCID mouse xenograft models of Acute Myeloid Leukemia (AML), Burkitt's Lymphoma (BL), and Diffuse Large B-cell Lymphoma (DLBCL), including drug-resistant human tumor in a PDX model. In mice, PCLX-001 produced complete remission of most xenografts at ≥35 mg/kg/day but also produced some deaths associated with bacterial infection and GI hemorrhage. In an AML xenograft mouse model, the drug exposure from oral dosing required to achieve 91% tumor inhibition was 3,423 ng*hr/mL (AUC (0-tlast)). When expressed on the basis of body surface area, the efficacious dose in mice was ≥105 mg/m2. To support clinical development, we evaluated PCLX-001 for safety in 4-week oral toxicity studies with 2-week recovery periods in rats at 50, 125, and 300 mg/kg/day and dogs at 2, 4, 8, and 12 mg/kg/day, performed to Good Laboratory Practice (GLP) standards. The highest non-severely toxic dose levels (HNSTDs) were 125 mg/kg/day for male rats, 300 mg/kg/day for female rats, and 4 mg/kg/day for dogs of both sexes. At higher dose levels, dose-limiting toxicity occurred within the first few days, was similar in both species, and was attributed to GI mucosal damage and decreased hematopoiesis, with secondary complications such as dehydration and inflammation. In dogs, systemic exposure to PCLX-001 increased more-than-proportionally with dose level after the first dose and did not change with repeated daily dosing. After the last dose at the HNSTD, Cmax averaged 651 ng/mL and 24-hour AUC averaged 3,760 h*ng/mL. In rats, systemic exposure to PCLX-001 after the first dose increased approximately proportionally with dose level and was much greater in males than females at all dose levels. With repeated daily dosing, exposure decreased dramatically in male rats but less so in female rats. As a result, exposure to PCLX-001 was similar in rats of both sexes after the last dose. After the last dose at the HNSTD in males and females, Cmax was 1650 and 8510 ng/mL, respectively, and 24-hour AUC averaged 6470 and 7590 h*ng/mL, respectively. When expressed on the basis of body surface area, the HNSTDs in male rats, female rats, and dogs were 750, 1800, and 80 mg/m2, respectively. As recommended in the ICH S9 Guidance, we chose a starting dose level of 20 mg/m2 for the first clinical trial because this was approximately 1/6th of the HNSTD in dogs. Given the dissimilarity of results between species, we compared the sequence of the NMTs in each since their inhibition was the target for PCLX-001. There was no significant difference between species in their sequence homology to humanNMT1(dog was 98%, rat 97% and mouse 99%), but dogNMT2had only 78% identity to humanNMT2while rat and mouseNMT2had 95% identity with humanNMT2. The significance of this dissimilarity is still under investigation. Disclosures Weickert: Pacylex Pharmaceuticals, Inc.:Current Employment, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees.Dillberger:Pacylex Pharmaceuticals, Inc.:Consultancy.Mackey:Pacylex Pharmaceuticals, Inc.:Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees.Berthiaume:Pacylex Pharmaceuticals, Inc.:Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees.

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