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9ms
PBRM1 loss is associated with increased sensitivity to MCL1 and CDK9 inhibition in clear cell renal cancer. (PubMed, Front Oncol)
Increased MCL1 activity has been described as a resistance mechanism to Sunitinib and Everolimus, two approved agents for ccRCC. PRT2527, a potent CDK9 inhibitor which depletes MCL1, was similarly efficacious in monotherapy and in combination with Sunitinib in PBRM1-loss cells. Taken together, these findings suggest PBRM1 loss is associated with MCL1i sensitivity in ccRCC and provide rationale for the evaluation of PRT1419 and PRT2527 for the treatment for PBRM1-deficient ccRCC.
Journal • IO biomarker
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BCL2 (B-cell CLL/lymphoma 2) • PBRM1 (Polybromo 1)
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PBRM1 mutation
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sunitinib • everolimus • PRT1419 • PRT2527
over1year
MCL1 inhibitor PRT1419 demonstrates anti-tumor activity in PBRM1-altered clear cell renal cancer and synergizes with standard of care agents (AACR 2023)
PRT1419 synergized with both Sunitinib and Everolimus in inhibiting tumor growth in various models. Taken together, these findings suggest PBRM1 loss is associated with sensitivity to MCL1 inhibition in ccRCC and provide rationale for the evaluation of PRT1419 for the treatment for PBRM1-deficient ccRCC
IO biomarker
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BCL2 (B-cell CLL/lymphoma 2) • PBRM1 (Polybromo 1)
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PBRM1 mutation • MCL1 expression
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sunitinib • everolimus • PRT1419
2years
PRMT5 Inhibition Alters Mitochondrial Dynamics in Mantle Cell Lymphoma Creating Vulnerability to BH3 Mimetic Compounds (ASH 2022)
Selectively inhibiting PRMT5 has shown significant anti-tumor activity in preclinical MCL models, and a Phase 1 clinical trial with PRT543 (Prelude), a novel PRMT5 inhibitor, is underway...Combinatorial treatment was tested in vivo using the PDX.AA.MCL model of ibrutinib resistant MCL...Navitoclax and PRT808 single agent as well as PRT808+PRT1419 regimens significantly slowed disease progression...Of note, navitoclax dosing alone or in combination did not induce additional platelet loss. Our results provide rationale for combining BH3 mimetics and PRMT5 inhibition in clinical trials as a novel treatment strategy for MCL.
IO biomarker
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BCL2 (B-cell CLL/lymphoma 2) • BCL2L1 (BCL2-like 1) • BCL2L2 (BCL2 Like 2) • PRMT5 (Protein Arginine Methyltransferase 5) • BBC3 (BCL2 Binding Component 3) • E2F1 (E2F transcription factor 1) • RELA (RELA Proto-Oncogene)
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BCL2 expression • MCL1 expression
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Imbruvica (ibrutinib) • navitoclax (ABT 263) • PRT1419 • PRT543
2years
NA1-115-7, from Zygogynum pancheri, is a new selective MCL-1 inhibitor inducing the apoptosis of hematological cancer cells but non-toxic to normal blood cells or cardiomyocytes. (PubMed, Biomed Pharmacother)
Synthetic inhibitors targeting these proteins have been developed, and some hematological malignancies are now widely treated with a BCL-2 inhibitor (venetoclax)...Six MCL-1 inhibitors (S64315, AZD-5991, AMG-176, AMG-397, ABBV-467 and PRT1419) have been evaluated in clinical trials since 2016, but some were affected by safety issues and none are currently used clinically...Importantly, a similar treatment with NA1-115-7 was not toxic to erythrocytes, peripheral blood mononuclear cells, platelets, or cardiomyocytes. These results highlight the potential of natural products for use as specific BH3 mimetics non-toxic to normal cells, and they suggest that NA1-115-7 may be a promising tool for use in cancer treatment.
Journal • IO biomarker
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BCL2L1 (BCL2-like 1)
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MCL1 expression
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Venclexta (venetoclax) • AZD5991 • tapotoclax (AMG 176) • PRT1419 • ABBV-467 • MIK665 • murizatoclax (AMG 397)
over2years
Combination of the MCL1 inhibitor PRT1419 and SMARCA2 degrader PRT3789 shows combinatorial benefit in SMARCA4 deleted lung cancer (AACR 2022)
In a broader lung cancer cell line viability screen conducted with PRT1419, we observed that the presence of multiple, co-occurring alterations in SWI/SNF family members such as SMARCA4, ARID1A/B mutations and loss of SMARCA2 protein were associated with sensitivity to PRT1419. Based on these findings, preclinical evaluation of PRT1419 in other tumor types with recurrent SWI/SNF mutations is ongoing.
IO biomarker
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BCL2 (B-cell CLL/lymphoma 2) • ARID1A (AT-rich interaction domain 1A) • SMARCA4 (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily A, member 4) • ARID1B (AT-Rich Interaction Domain 1B) • ARID2 (AT-Rich Interaction Domain 2) • SMARCA2 (SWI/SNF Related, Matrix Associated, Actin Dependent Regulator Of Chromatin, Subfamily A, Member 2)
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ARID1A mutation • SMARCA4 mutation • SMARCA4 deletion • MCL1 amplification
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PRT1419 • PRT3789
over3years
[VIRTUAL] Preclinical characterization of PRT1419, a potent, selective and orally available inhibitor of MCL1 (AACR 2021)
Importantly, MCL1 has been implicated in mediating resistance to chemotherapy as well as targeted therapies, including the BCL2 inhibitor, venetoclax. Further, PRT1419 demonstrated synergistic activity with tyrosine kinase inhibitors to inhibit the proliferation of breast, melanoma, and non-small cell lung cancer cell lines. PRT1419 is currently under evaluation in a Phase I clinical trial in patients with relapsed/refractory hematologic malignancies (NCT04543305).
Preclinical • PARP Biomarker • IO biomarker
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BCL2L1 (BCL2-like 1) • CASP3 (Caspase 3)
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MCL1 expression
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Venclexta (venetoclax) • PRT1419