SHIN1 (RZ2994) is an inhibitor of serine hydroxymethyltransferase 1 (SHMT1) and SHMT2, with IC50 values of 5nM and 13nM, respectively[1, 2]. SHIN1 can competitively bind to folate, penetrate cell membranes, and exhibits anti-cancer activity[3].
In vitro, treatment of murine peritoneal macrophages with SHIN1 (10μM) for 6h dose-dependently reduced the LPS-induced increase in IL-1β and IL-1α mRNA expression, as well as precursor IL-1β protein levels, without affecting TNF-α[4]. Treatment of human keratinocyte cell line HaCaT cells with SHIN1 (2μM) for 24h significantly reduced the IL-17-induced increase in Defb4, Lcn2, S100a9, and IL-1β expression[5].
In vivo, intraperitoneal injection of SHIN1 (100mg/kg/day) for 14 days in mice bearing RPMI8402 xenograft tumors significantly reduced leukemia burden in the bone marrow and spleen[6].
References:
[1] He L, Endress J, Cho S, et al. Suppression of nuclear GSK3 signaling promotes serine/one-carbon metabolism and confers metabolic vulnerability in lung cancer cells[J]. Science advances, 2022, 8(20): eabm8786.
[2] Ducker G S, Ghergurovich J M, Mainolfi N, et al. Human SHMT inhibitors reveal defective glycine import as a targetable metabolic vulnerability of diffuse large B-cell lymphoma[J]. Proceedings of the National Academy of Sciences, 2017, 114(43): 11404-11409.
[3] García-Cañaveras J C, Lancho O, Ducker G S, et al. SHMT inhibition is effective and synergizes with methotrexate in T-cell acute lymphoblastic leukemia[J]. Leukemia, 2021, 35(2): 377-388.
[4] Yu W, Wang Z, Zhang K, et al. One-carbon metabolism supports S-adenosylmethionine and histone methylation to drive inflammatory macrophages[J]. Molecular cell, 2019, 75(6): 1147-1160. e5.
[5] Lee J Y, Lee J H, Lim H J, et al. Aminooxy acetic acid suppresses Th17-mediated psoriasis-like skin inflammation by inhibiting serine metabolism[J]. Frontiers in Pharmacology, 2023, 14: 1215861.
[6] Pikman Y, Ocasio-Martinez N, Alexe G, et al. Targeting serine hydroxymethyltransferases 1 and 2 for T-cell acute lymphoblastic leukemia therapy[J]. Leukemia, 2022, 36(2): 348-360.
SHIN1（RZ2994）是丝氨酸羟甲基转移酶1（SHMT1）和SHMT2的抑制剂，IC50分别为5nM和13nM[1, 2]。SHIN1能够与叶酸竞争结合、能够穿透细胞膜，具有抗癌活性[3]。
在体外，SHIN1（10μM）处理小鼠腹腔巨噬细胞6h，剂量依赖性地降低了LPS诱导的IL-1β和IL-1α mRNA表达水平升高，以及前体IL-1β蛋白，但未影响TNF-α[4]。SHIN1（2μM）处理人表皮角质细胞系HaCaT细胞24h，显著降低了IL-17刺激引起的Defb4、Lcn2、S100a9和IL-1β表达水平升高[5]。
在体内，SHIN1（100mg/kg/day）通过腹腔注射治疗RPMI8402细胞异种移植小鼠14天，显著降低了小鼠骨髓和脾脏中的白血病负担[6]。