2. GPCR/G Protein MAPK/ERK Pathway Metabolic Enzyme/Protease Stem Cell/Wnt Apoptosis
  3. Ras Phosphatase ERK Apoptosis
  4. BBO-11818

BBO-11818 是一种口服有效、高选择性 (相对于 NRAS 和 HRAS 而言)、非共价的泛 KRAS 抑制剂 (IC50=28-120 nM)。BBO-11818 能特异性结合 Switch-II/Helix 3 口袋，通过诱导构象变化破坏 KRAS:RAF1 相互作用并阻断 MAPK 信号通路。BBO-11818 具有显著的抗肿瘤活性，不仅能抑制细胞增殖、诱导凋亡 (apoptosis)，还能在异种移植模型中驱动肿瘤消退。BBO-11818 与 Cetuximab (HY-P9905)、抗-PD-1 抗体或 PI3Kα 抑制剂等联用时具有协同增效作用。BBO-11818 已被用于胰腺癌、非小细胞肺癌及结直肠癌等 KRAS 突变相关恶性肿瘤的研究。

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BBO-11818

BBO-11818 Chemical Structure

CAS No. : 3029443-36-2

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1 mg ￥8360
9 - 11 周
5 mg 询价 9 - 11 周
10 mg 询价 9 - 11 周
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BBO-11818 相关抗体

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  • 生物活性

  • 纯度 & 产品资料

  • 参考文献

生物活性

BBO-11818 is an orally active, highly selective (relative to NRAS and HRAS), non-covalent pan-KRAS inhibitor (IC50=28-120 nM). BBO-11818 specifically binds to the Switch-II/Helix 3 pocket, disrupts the KRAS:RAF1 interaction by inducing conformational changes, and blocks the MAPK signaling pathway. BBO-11818 exhibits significant anti-tumor activity, which not only inhibits cell proliferation and induces apoptosis, but also drives tumor regression in xenograft models. BBO-11818 produces synergistic effects when combined with Cetuximab (HY-P9905), anti-PD-1 antibody or PI3Kα inhibitor. BBO-11818 is used in the research of KRAS mutation-related malignancies such as pancreatic cancer, non-small cell lung cancer and colorectal cancer[1][2].

IC50 & Target

K-Ras WT

28 nM (IC50)

KRAS(G12D)

61 nM (IC50)

KRas G12V

47 nM (IC50)

KRAS(G12C)

51 nM (IC50)

KRas G12R

120 nM (IC50)

体外研究
(In Vitro)

BBO-11818 (2.5 nM; 21 d) 可抑制 Capan-2 PDAC (KRASG12V) 细胞的长期克隆形成生长[1]。
BBO-11818 (3 nM; 15 d) 可抑制 LS513 结直肠癌 (KRASG12D) 细胞的长期克隆形成生长[1]。
BBO-11818 (30 nM; 4 h) 可强效且选择性地抑制 SOS 介导的 KRAS (野生型和致癌突变体) 核苷酸交换，包括组成型结合 GTP 的 KRASA59G 突变体，但对 NRAS 无活性[2]。
BBO-11818 (0.1-200 nM; 96 h) 可强效抑制由野生型或致癌 KRAS 突变体 (包括组成型结合 GTP 的 KRASA59G) 驱动的 Ba/F3 细胞的活力，而在 KRASG12R 和 KRASQ61X 突变体中的活性有所降低[2]。
BBO-11818 (0-0.1 μM; 72h & 96 h) 可强效且选择性地抑制由致癌 KRAS 突变或 KRAS 扩增驱动的人类癌细胞系的 3D 球状体生长，而在非 KRAS 驱动的细胞系中活性极低[2]。

MCE has not independently confirmed the accuracy of these methods. They are for reference only.

BBO-11818 相关抗体:

Cell Viability Assay[2]

Cell Line: KRAS-dependent Ba/F3 cell lines (KRASG12A, G12D, G12R, G12S, G12V, G13D, A59G, Q61H, Q61K, Q61L, WT)
Concentration: 11-point 1:3 dose titration
Incubation Time: 96 h
Result: Potently inhibited viability in KRAS-dependent Ba/F3 cell lines with the following EC50 values: KRASG12A (0.824 nmol/L), KRASG12D (1.33 nmol/L), KRASG12S (0.505 nmol/L), KRASG12V (5.84 nmol/L), KRASG13D (1.13 nmol/L), KRASA59G (3.28 nmol/L), KRAS WT (8.99 nmol/L).
Showed reduced activity in KRASG12R (22.9 nmol/L), KRASQ61H (53.3 nmol/L), KRASQ61K (48.4 nmol/L), and KRASQ61L (136 nmol/L) cell lines.

Cell Viability Assay[2]

Cell Line: Human cancer cell lines (KRASG12D, G12V, G12C, G12A, G12R, G12S, G13D, Q61X, KRASAMP, HRASmut, NRASmut, BRAFmut)
Concentration: Nine-point 1:3 dose titration
Incubation Time: 72-hour spheroid formation, 96-hour incubation
Result: Potently inhibited 3D spheroid viability in KRAS-mutant and KRASAMP cell lines with the following mean EC50 values: KRASG12D (2.21 nmol/L), KRASG12V (31.2 nmol/L), KRASG12C (2.26 nmol/L), KRASG12A (5.32 nmol/L), KRASG12S (3.09 nmol/L), KRASG13D (71.7 nmol/L), KRASAMP (7.62 nmol/L).
Showed limited activity in KRASG12R (400 nmol/L) and KRASQ61X (3170 nmol/L) cell lines, and minimal activity in HRASmut (4030 nmol/L), NRASmut (3720 nmol/L), and BRAFmut (7430 nmol/L) cell lines.
体内研究
(In Vivo)

BBO-11818 (10-100 mg/kg; p.o.; BID; 28 d) 可在携带 KRASG12D 突变的 HPAC 胰腺癌 CDX 模型中诱导强效且具有统计学意义的肿瘤生长抑制和肿瘤消退[1]。
BBO-11818 (10-100 mg/kg; p.o.; BID; 28 d) 可在 KRASG12V 突变型 Capan-2 胰腺癌 CDX 模型中诱导呈剂量依赖性、具有统计学显著性的肿瘤生长抑制作用[1]。
BBO-11818 (10-100 mg/kg; p.o.; BID; 28 d) 可在 KRASG12D/PIK3CAH1047L 突变型 GP2d 结直肠癌 CDX 模型中诱导强效且具有统计学意义的肿瘤生长抑制和肿瘤消退[1]。
BBO-11818 (10-100 mg/kg; p.o.; BID; 28 d) 可在携带 KRASG12V 突变的 H441 非小细胞肺癌 CDX 模型中诱导强效、剂量依赖性且具有统计学意义的肿瘤生长抑制作用[1]。
BBO-11818 (10-100 mg/kg; p.o.; 单次) 可在 KRASG12D 突变型 HPAC 胰腺癌 CDX 模型中，以剂量依赖的方式 (降至溶媒组的~10%) 且持续地 (长达 24 h) 抑制 pERK 的活性[1]。
BBO-11818 (100 mg/kg; p.o.; BID) 可在 KRASG12V 突变型 Capan-2 胰腺癌 CDX 模型中诱导肿瘤细胞增殖出现统计学意义的降低，并促进细胞凋亡水平升高[1]。
BBO-11818 (100 mg/kg; p.o.; BID; 28 d) 联合 anti-PD-1 抗体 (10 mg/kg; i.p.; BIW) 可改善 KRASG12D 突变型 CT26 结直肠癌同源模型的存活率[1]。
BBO-11818 (10-100 mg/kg; p.o.; 单次) 可在 KRASG12D 胰腺癌 (PDAC) 异种移植物中产生剂量和时间依赖性的 pERK 与 DUSP6 抑制作用，其中 pERK 抑制的体内 EC50 为 138 nmol/L，单次 100 mg/kg 口服剂量下 pERK 水平最高可降低 85%[2]。
BBO-11818 (10-100 mg/kg; p.o.; 每天 2 次; 28 d) 在 KRASG12D 胰腺导管腺癌 (PDAC) 异种移植模型中经每日两次给药后展现出强劲的抗肿瘤功效，在 100 mg/kg 每日两次的剂量下实现了 57% 的平均肿瘤消退，且每日两次给药的 ED50 为 9 mg/kg[2]。
BBO-11818 (10-100 mg/kg; p.o.; 每天 2 次; 28 d) 在 KRASG12D/PIK3CAH1047L 结直肠癌异种移植物模型中展现出强效抗肿瘤活性，每日给药两次时，100 mg/kg 每日两次的剂量可实现 69% 的平均肿瘤退缩，其每日两次给药的 ED50 为 6.7 mg/kg[2]。
BBO-11818 (10-100 mg/kg; p.o.; 每天 2 次; 28 d) 在 KRASG12V 非小细胞肺癌异种移植模型中展现出强大的抗肿瘤功效，每日给药两次时，100 mg/kg 每日两次的剂量下可达到 99% 的 TGI，且每日两次给药的 ED50 为 11.6 mg/kg[2]。
BBO-11818 (100 mg/kg; p.o.; 每天 2 次; 28 d) 以 100 mg/kg 每日两次的剂量给药时，可将 KRASG12D 同源结直肠癌小鼠的中位生存期延长至 25 天 (对照组为 19 天)；与抗 PD-1 联合使用时，可将中位生存期延长至 50 天，并在治愈小鼠中诱导持久的适应性免疫[2]。
BBO-11818 (100 mg/kg; p.o.; 每天 2 次; 28 d) 在 KRASG12V 胰腺癌异种移植模型中以 100 mg/kg 每日两次的单药治疗方案实现了 83% 的 TGI，与 100 mg/kg 每日一次的 BBO-10203 联用时则可驱动 40% 的平均肿瘤消退[2]。
BBO-11818 (100 mg/kg; p.o.; 每天 2 次; 21 d) 在 KRASG12D 非小细胞肺癌 (NSCLC) PDX 肿瘤中以 100 mg/kg 每日两次的给药方案达到 95% 的 TGI；当与 100 mg/kg 每日一次的 BBO-10203 联用时，可实现 63% 的平均肿瘤消退[2]。
BBO-11818 (30 mg/kg; p.o.; 每天 2 次; 21 d) 在 KRASG12D 结直肠癌异种移植模型中以 30 mg/kg 每日两次的单药治疗方案实现了 89% 的 TGI，与 15 mg/kg 每周两次的西妥昔单抗联合使用时可诱导 57% 的平均肿瘤消退[2]。
BBO-11818 (100 mg/kg; p.o.; 2 次) 可降低 KRASG12V 胰腺癌 (PDAC) 异种移植模型中的肿瘤细胞增殖并促进细胞凋亡；在每日两次给予 100 mg/kg、给药 1 天后的 24 小时，其可使 BrdU 阳性区域减少 57%，裂解的 caspase-3 阳性区域增加 81%；当与 BBO-10203 联用时，该药物可进一步增强上述作用，使 BrdU 阳性区域减少 85%、caspase-3 阳性区域增加 107%[2]。

MCE has not independently confirmed the accuracy of these methods. They are for reference only.

Animal Model: Immunocompromised mice[1]
Dosage: 10 mg/kg; 30 mg/kg; 100 mg/kg
Administration: p.o.; BID; 28 days
Result: Achieved 56% tumor growth inhibition (TGI) at 10 mg/kg BID, with statistical significance (p<0.0001 vs vehicle).
Achieved 87% TGI and 57% mean tumor regression (REG) at 30 mg/kg BID, with statistical significance (p<0.0001 vs vehicle).
Achieved 87% TGI and 57% REG at 100 mg/kg BID, with statistical significance (p<0.0001 vs vehicle).\nAchieved 14% tumor growth inhibition (TGI) at 10 mg/kg BID, with statistical significance relative to vehicle.
Achieved 42% TGI at 30 mg/kg BID, with statistical significance relative to vehicle.
Achieved 81% TGI at 100 mg/kg BID, with statistical significance relative to vehicle.
Animal Model: Immunocompromised mice[1]
Dosage: 10 mg/kg; 30 mg/kg; 100 mg/kg
Administration: p.o.; single dose
Result: Reduced pERK to ~80% of vehicle at 6 hours post 10 mg/kg dose, with statistical significance relative to vehicle.
Reduced pERK to ~50% of vehicle at 6 hours post 30 mg/kg dose, with statistical significance relative to vehicle.
Reduced pERK to ~10% of vehicle at 6 hours post 100 mg/kg dose, with statistical significance relative to vehicle.
Sustained pERK inhibition at 100 mg/kg, with levels remaining at ~20-30% of vehicle at 2, 6, 12, and 24 hours post-dose, all with statistical significance relative to vehicle.
Animal Model: BALB/c nude[2]
Dosage: 10 mg/kg; 30 mg/kg; 100 mg/kg
Administration: p.o.; single dose
Result: Reduced tumor pERK levels by 27% at 6 hours post 10 mg/kg dose relative to vehicle.
Reduced tumor pERK levels by 45% at 6 hours post 30 mg/kg dose relative to vehicle.
Reduced tumor pERK levels by 85% at 6 hours post 100 mg/kg dose relative to vehicle.
Reduced tumor DUSP6 mRNA levels by 27% at 6 hours post 10 mg/kg dose relative to vehicle.
Reduced tumor DUSP6 mRNA levels by 54% at 6 hours post 30 mg/kg dose relative to vehicle.
Reduced tumor DUSP6 mRNA levels by 84% at 6 hours post 100 mg/kg dose relative to vehicle.
Reduced pERK levels by 67%, 85%, 81%, and 77% at 2, 6, 12, and 24 hours post 100 mg/kg dose relative to vehicle, respectively.
Reduced DUSP6 levels by 60%, 84%, 81%, and 66% at 2, 6, 12, and 24 hours post 100 mg/kg dose relative to vehicle, respectively.
Achieved an in vivo EC50 of 138 nmol/L and EC90 of 411 nmol/L for pERK inhibition.
Animal Model: BALB/c nude[2]
Dosage: 100 mg/kg
Administration: p.o.; twice daily; single day
Result: Reduced BrdU-positive tumor area by a statistically significant amount relative to vehicle at 6 hours post-dose as monotherapy.
Reduced BrdU-positive tumor area by 57% relative to vehicle and increased cleaved caspase-3-positive tumor area by 81% relative to vehicle at 24 hours post-dose as monotherapy.
Reduced BrdU-positive tumor area by 85% relative to vehicle and increased cleaved caspase-3-positive tumor area by 107% relative to vehicle at 24 hours post-dose when combined with 100 mg/kg once daily BBO-10203; this combination effect was statistically significant compared with monotherapies.
分子量

733.73

Formula

C34H33F6N7O3S
CAS 号
运输条件

Room temperature in continental US; may vary elsewhere.
储存方式

Please store the product under the recommended conditions in the Certificate of Analysis.
纯度 & 产品资料
参考文献

BBO-11818 相关分类

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Keywords:

BBO-118183029443-36-2BBO11818BBO 11818RasPhosphataseERKApoptosisExtracellular signal regulated kinasesMAPK signalingnon-small cell lung cancerRAF1ERK phosphorylationHRASxenograft modelsKRASpancreatic cancerNRAScolorectal cancerInhibitorinhibitorinhibit

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