AACR19简单收尾之新靶点聚焦
回到AACR的初衷，基本都是临床前的动物甚至体外研究数据，没找到presentation和poster的图，所以就把这些冰冷的链接贴了出来，算是给AACR19系列简单收个尾。这里先做一个汇总，将来有了published data再一一详细回看。
AMGEN-AMG-510 KRAS G12C inhibitor
ABBIVE-ABBV155 Bcl-XL inhibitor
JNJ- GPRC5D/CD3 bispecific antibody
LILLY-LY3295668 Aurora-A inhibitor
MERK.DE-M3258 LMP7 inhibitor
AZN-AZD7648 DNA-PK Inhibitor
Five Prime-CD80 Fc
Takeda-TAK-981 SUMOylation inhibitor
BI-BI 905677 LPR5/6 Antagonist
CellCentric Ltd-p300/CBP Bromo inhibitor
AMGEN-AMG-510 KRAS G12C inhibitor
4484- Discovery and in vitro characterization of AMG 510--a potent and selectivecovalent small-molecule inhibitor of KRASG12C
https://www.abstractsonline.com/pp8/#!/6812/presentation/1929
Abstract
Activating mutations in RAS represent themost common oncogenic driver mutation in cancer. The single amino acid substitution of cysteine for glycine at position 12 (KRASG12C) is frequently found in solid malignancies, particularly in lung adenocarcinoma(~13%), colorectal adenocarcinoma (3%), and pancreatic adenocarcinoma (~1%).Recently it has been demonstrated that KRASG12C can be targeted with covalent small molecule inhibitors which react with the mutant cysteine adjacent to the switch II pocket (SIIP), locking KRAS in its inactive GDP-bound state. We describe here the discovery and in vitro characterization of AMG 510, a covalent inhibitor of KRASG12C possessing potent biochemical and cellular activity, as well as robust in vivo efficacy.AMG 510 inhibited SOS1-catalyzed nucleotide exchange of recombinant mutant KRASG12C/C118A buthad minimal effect on KRASC118A, which is wildtype at position 12. The observed rate constant (kinact/Ki) of covalent modification of KRASG12C by AMG 510 was determined biochemically by mass spectrometry as well as in the cellular context (kobs/[I]). Cysteine proteome analysis of cells treated with AMG 510 revealed that only the G12C-containing peptide of KRAS was covalently modified. AMG 510 inhibited KRAS signaling as measured by ERK phosphorylation in all KRAS p.G12C celllines tested, but did not inhibit phosphorylation of ERK in cell lines lackingthe KRAS p.G12C mutation. Cellular occupancy of KRASG12C byAMG 510 was determined by mass spectrometry and correlated well with inhibitionof ERK phosphorylation. AMG 510 also selectively impaired the viabilityof KRAS p.G12C mutant lines. Combination treatment of AMG 510with inhibitors of other cellular signaling pathways exhibited evidence forsynergistic effects on cell viability. Treatment of KRAS p.G12C lineswith covalent KRASG12C inhibitors increased the expression of HLA. To test the impactof KRASG12C inhibition on immune surveillance in vivo, wegenerated a syngeneic tumor cell line that is suitable for testing AMG 510 incombination with checkpoint inhibitor therapies and characterized thisline in vitro. AMG 510 is currently being evaluated in a Phase Istudy in patients with solid tumors harboring KRAS p.G12C mutations.
3090 / 24 - In vivo characterization of AMG 510 - a potent and selective KRASG12Ccovalent small molecule inhibitor in preclinical KRASG12Ccancer models
https://www.abstractsonline.com/pp8/#!/6812/presentation/7598
Abstract
Somatic activating mutations of RAS family members are tumor driver mutations found in an estimated 21% of all cancers. Oncogenic KRAS mutations at residues G12, G13, and Q61 represent the most common RAS mutations found in solid malignancies. The prevalence of KRAS p.G12C tumors is~13% of lung adenocarcinoma (including NSCLC), 3% of colorectal carcinoma(CRC), and 1% to 2% of numerous other solid tumors, representing an unmet medical need. We have developed AMG 510, an orally bioavailable, covalent inhibitor of KRASG12C with potent biochemical and cellular activity, and robust in vivo efficacy. AMG 510 inhibited SOS-catalyzed nucleotide exchange of recombinant mutant KRASG12C/C118A but had minimal effect on KRASC118A, which is wildtype at position 12. Incellular assays, AMG 510 covalently modified KRASG12C and inhibited KRASG12C signaling as measured by phosphorylation of ERK1/2 (p-ERK) in all KRAS p.G12C-mutant cell lines tested but did not inhibit p-ERK in cell lines with various other KRAS mutations. AMG 510 also selectively impaired viability of KRAS p.G12C mutant cell lines but did not affectcell lines with other KRAS mutations. In vivo pharmacodynamic assays demonstrated dose- and time-dependent inhibition of KRASG12C signaling in human pancreatic and NSCLC tumor xenografts. Covalent modification of KRASG12C by AMG 510 was measured by mass spectrometry and correlated with p-ERK inhibition in tumors. AMG 510 significantly inhibited the growth of KRASp.G12C xenografts and resulted in tumor regression. Combination treatment of AMG 510 with standard-of-care and targeted agents demonstrated enhanced tumor growth inhibition compared to either single agent. In asyngeneic model of KRAS p.G12C mutant cancer, AMG 510treatment significantly inhibited tumor growth and caused regression. AMG 510is currently in Phase 1, first-in-human clinical trials for patients with advanced solid tumors harboring a KRAS p.G12C mutation.
4455- Discovery of AMG 510, a first-in-human covalent inhibitor of KRASG12C for the treatment of solidtumors
https://www.abstractsonline.com/pp8/#!/6812/presentation/2772
Abstract
The RAS gene family encodes the small GTPase proteins NRAS, HRAS, and KRAS, which play an essential role in cellular growth and proliferation. KRAS is one of the most frequently mutated oncogenes in human cancer, with KRAS p.G12D, p.G12V,and p.G12C constituting the major mutational subtypes acrosslung, colon, and pancreatic cancers. Despite more than three decades of research, indirect approaches targeting KRAS mutant cancer shave largely failed to show clinical benefit, and direct approaches have been stymied by the apparently ‘undruggable’ nature of KRAS. Cysteine-12 of KRASG12C has recently emerged as a unique vulnerability in KRAS-mutant cancers,and a small number of cysteine-reactive inhibitory tool molecules have been disclosed. We here report independent efforts to identify cysteine-reactive molecules capable of selectively inhibiting KRASG12C. Through iterative screening and structural biology efforts, we identified a novel Cys12-reactive inhibitor scaffold that derived its potency from occupancy of a previously unknown cryptic pocket induced by side-chain motion of the His95 residue of KRAS. Employing a scaffold-hopping approach, we leveraged knowledge of this cryptic pocket to design a series of N-arylquinazolin-2(1H)-one-based inhibitors that demonstrated significantly enhanced potency relative to prior tool compounds. Extensive optimization of these leadsled to the identification of a highly potent, selective, and well-tolerated inhibitor of KRASG12C, which was nominated for clinical development as AMG 510. In preclinical tumor models, AMG 510 rapidly and irreversibly binds to KRASG12C, providing durable suppression of the mitogen-activated protein kinase (MAPK) signaling pathway.Dosed orally (once daily) as a single agent, AMG 510 is capable of inducing tumor regression in mouse models of KRASG12C cancer. AMG 510is, to the best of our knowledge, the first direct KRASG12C therapeutic to reach human clinical testing and is currently in a Phase I clinical trial evaluating safety, tolerability, PK, and efficacy in subjects with solid tumors bearing the KRAS p.G12C mutation (NCT03600883).
ABBIVE-ABBV155 Bcl-XL inhibitor
ABBV-155: A first-in-class BCL-XL inhibitor antibody drug conjugate
https://www.abstractsonline.com/pp8/#!/6812/presentation/9844
March 31, 2019, 4:52 PM - 5:15 PM
JNJ- GPRC5D/CD3 bispecific antibody
Development of GPRC5D/CD3 bispecific antibody for the treatment of multiple myeloma
March 31, 2019, 4:04 PM - 4:28 PM
https://www.abstractsonline.com/pp8/#!/6812/presentation/7603
LILLY-LY3295668 Aurora-A inhibitor
LY3295668: An exquisitely selective Aurora-Ainhibitor for the treatment of cancers with aberrations in RB1 and other cellcycle genes
March 31, 2019, 3:40 PM - 4:04 PM
https://www.abstractsonline.com/pp8/#!/6812/presentation/7602
CT019 / 14 - Population pharmacokinetics ofan aurora kinase A inhibitor, LY3295668 erbumine (AK-01), in patients with locally advanced or metastatic solid tumors
March 31, 2019, 1:00 PM - 5:00 PM
https://www.abstractsonline.com/pp8/#!/6812/presentation/9926
CT083 / 7 - A Phase I/II study of aurorakinase A inhibitor, LY3295668 erbumine (AK-01): Safety as monotherapy inpatients with locally advanced or metastatic solid tumors
https://www.abstractsonline.com/pp8/#!/6812/presentation/9891
April 1, 2019, 1:00 PM - 5:00 PM
MERK.DE-M3258 LMP7 inhibitor
LB-054. Discovery and profiling of M3258, apotent and selective LMP7 inhibitor demonstrating high efficacy in multiple myeloma models
March 31, 2019, 3:00 PM - 5:00 PM
https://www.abstractsonline.com/pp8/#!/6812/presentation/9403
DDT02-01. First-time disclosure of M3258: Aselective inhibitor of the immunoproteasome subunit LMP7 with potential forimproved therapeutic utility in multiple myeloma compared to pan-proteasome inhibitors
March 31, 2019, 3:16 PM - 3:40 PM
https://www.abstractsonline.com/pp8/#!/6812/presentation/7601
AZN-AZD7648 DNA-PK Inhibitor
DDT01-02- Discovery and first structural disclosure of AZD7648: A potent and selective DNA-PK inhibitor
March31, 2019, 1:24 PM - 1:48 PM
https://www.abstractsonline.com/pp8/#!/6812/presentation/7590
Abstract
DNA-dependent kinase (DNA-PK) plays an important role in the cellular response to DNA damage through the detection andrepair of double strand breaks, and is a critical component of the DNA damage response (DDR). Double strand breaks can be induced by a range of agents,including chemotherapy, radiation or PARP inhibitors such as olaparib(Lynparza), and thus a DNA-PK inhibitor is likely to sensitise to these agents.DNA-PK inhibitors may also be effective as monotherapy in tumours with high endogenous levels of DNA damage resulting from defects in other DNA repair pathways. Our screening strategy focussed on identifying hits with good selectivity versus structurally related kinases. Significant improvements were made to permeability, metabolic stability and PK properties, whilst improving potency and selectivity with a structure-guided approach. This optimisation resulted in AZD7648, which is a potent inhibitor of DNA-PK (0.6 nM inbiochemical assay, 89 nM in A549 cells) and >100x selective against 396 otherkinases in a Thermofisher selectivity panel. In addition, AZD7648 has good crystalline solubility, metabolic stability and predictable pharmacokinetics inpreclinical species. In murine xenograft models, PD was assessed using pRPA(S4/8) and was potently inhibited (in vivo IC50 = 52 nM). Tumour growth inhibition was observed with AZD7648 as monotherapy, and regressions were observed in combination with either olaparib or radiation. The efficacy observed when combining AZD7648 with olaparib was correlated to free cover over the in vivo IC90. AZD7648 is a potent and highly selective DNA-PK inhibitor,with good crystalline solubility, permeability and metabolic stability, good bioavailability and predictable pharmacokinetics in preclinical species, and potent knockdown of pRPA and regressions in murine xenograft models when combining with olaparib or radiation. These features make AZD7648 a suitable clinical candidate, and clinical studies evaluating AZD7648 as a potential cancer treatment are planned in 2019.
3505/ 16 - AZD7648: A potent and selective inhibitor of DNA-PK with pharmacodynamic and monotherapy anti-tumor activity
https://www.abstractsonline.com/pp8/#!/6812/presentation/980
April2, 2019, 8:00 AM - 12:00 PM
Abstract
DNA-dependent kinase (DNA-PK) is a nuclear serine/threonine protein kinase complex that is a key component of the non-homologous end joining (NHEJ) process. DNA-PK plays an important role in the cellular response to DNA damage through the detection and repair of DNA double strand breaks (DSB) and is a critical component of the DNA Damage Response (DDR). DSB can be induced by a range of agents, including chemotherapy, radiation or Poly ADP Ribose Polymerase (PARP) inhibitors such as olaparib, and thus a DNA-PK inhibitor is likely to sensitize to these agents.DNA-PK inhibitors may also be effective as monotherapy in tumors with high endogenous levels of DNA damage resulting from defects in other DNA repair pathways. We have developed a highly potent and selective inhibitor of DNA-PK, AZD7648(pDNA-PK IC50 in A549 cells = 92 nM). AZD7648 shows broad growth inhibitory activity across a panel of 244 cancer cell lines (GI50 1.3 - 30 µM). Consistent with known synthetic lethal interactions with DNA-PK, AZD7648 shows a10-13-fold greater growth inhibitory effect in FaDu head and neck and A549non-small cell lung cancer cell lines with ATM knocked out (KO) by zinc fingernuclease or CRISPR respectively compared to their isogenic wild-type counterparts (WT). This growth inhibition is associated with increased levelsof DNA damage as measured by micronuclei formation detected using high-content immunofluorescence (2-fold increase vs DMSO at 2 µM AZD7648). Moreover, a 6-fold increase in chromosomal breaks are detected in the ATM KO cells using metaphase spread analysis (mean breaks/cell: FaDu ATM KO = 1.7, ATM WT = 0.28)In vivo, monotherapy treatment with AZD7648 (75-100 mg/kg bid) inhibited tumorgrowth in a panel of 14 PDX and 2 xenograft models, derived from breast, lung,ovarian and head and neck cancers. This included models with and without loss of ATM. Treatment with AZD7648 resulted in dose-dependent inhibition of the phosphorylation of DNA-PK (S2056), RPA32 (S4/8) and nuclear γH2AX in FaDu ATM KO xenografts, where AZD7648 75mg/kg inhibited γH2AX and phosphorylation of DNA-PK (S2056) and RPA32 (S4/8) by 71, 98 and 95% respectively at 2 h after dosing. These data confirm that DNAPK inhibition using AZD7648 has potent pharmacodynamic and monotherapy anti-tumor activity in a range of pre-clinicalmodels. This includes, but is not restricted to, models with engineered and endogenous loss of ATM.
3506/ 17 - AZD7648, a potent and selective inhibitor of DNA-PK, potentiates activity of the PARP inhibitor olaparib resulting in sustained anti-tumour activityin xenograft and PDX models
https://www.abstractsonline.com/pp8/#!/6812/presentation/981
April2, 2019, 8:00 AM - 12:00 PM
Abstract
DNA-dependent kinase (DNA-PK) is a nuclearserine/threonine protein kinase complex and a key component of the non-homologousend joining (NHEJ) process. DNA-PK plays an important role in the cellularresponse to DNA damage through the detection and repair of double strand breaks(DSB). DSB can be induced by a range of agents, including chemotherapy andradiation. The PARP inhibitor olaparib has also been shown to induce DSB as aconsequence of trapping PARP proteins at sites of damaged DNA. Therefore, wehypothesised that DNA-PK inhibitors may combine therapeutically with PARPinhibitors. AZD7648 is a highly potent and selective inhibitor of DNA-PK(pDNA-PK cell IC50 = 92 nM) The combination treatment of AZD7648 with olaparibfor 10 - 12 days in vitro leads to at least 20% greater cell growth inhibitioncompared with either agents as monotherapies in a panel of cell lines withdeficiencies in the ATM pathway (e.g. cells lacking ATM protein or where ATMsubstrates are not phosphorylated after exposure to DSB inducing agents). Thiseffect is also seen in isogenic ATM knock-out (KO) FaDu head and neck and A549non-small cell lung cancer cell lines. At concentrations of AZD7648 (0.6 - 2µM) and olaparib (1 µM) that have monotherapy activity in the ATM KO cells butnot in their wild-type counterparts (WT), the combination treatment enhancedthe G2/M cell cycle arrest caused by olaparib and led to greater levels ofmicronuclei formation as detected using high-content immunofluorescece assays(mean per cell: FaDu WT = 0.1, FaDu ATM KO = 0.4). This was associated with alarger quantity of chromosomal aberrations in the ATM KO versus WT cellsfollowing combination treatment detected by metaphase spread analysis (mean percell: FaDu ATM KO = 5.5, FaDu WT = 1.2). The same phenotype was observed inA549 ATM KO versus WT cell lines. In vivo, continuous dosing of AZD7648 (75mg/kg bid) in combination with olaparib (100 mg/kg qd) inhibited the growth ofFaDu WT tumours by ~60%. However, in the FaDu ATM KO tumours completeregressions were seen after 70 days of dosing and no re-growth was detected upto 220 days later. Additionally, in PDX models of breast, lung, ovarian andhead and neck cancer this combination showed tumour growth inhibition (50-100%)in 13 models and regression in 5 models, only one of these five models beingATM pathway deficient. These data confirm that DNA-PK inhibition using AZD7648enhances the efficacy of olaparib in vitro and in vivo, providing a clearrationale for its clinical investigation.
3511/ 22 - Exploration of pre-clinical relationships between pharmacokinetics, pharmacodynamics and tumor volume for the novel DNA-PK inhibitor AZD7648
https://www.abstractsonline.com/pp8/#!/6812/presentation/986
April2, 2019, 8:00 AM - 12:00 PM
Abstract
AZD7648 is a potent and highly selective inhibitor of DNA-dependent protein kinase (DNA-PK) that has been nominated for clinical development. DNA-PK is a nuclear serine/threonine protein kinase complex involved in DNA damage repair, and a key component of the non-homologous end joining repair mechanism of double strand breaks (DSBs).This work aimed to explore the relationships between pharmacokinetics (PK), pharmacodynamics (PD) and xenograft tumor volume from pre-clinical studies, in order to define PD requirements for pre-clinical efficacy, and to estimate a target clinical dose for AZD7648 in combination with DSB-inducing agents such as olaparib or pegylated liposomal doxorubicin (PLD). A population-based modelling approach was used to explore the PK of AZD7648 in mice. The PK model was developed using data from full PK profiles (multiple longitudinal samples per mouse), and validated against terminal sample PK data. The potential influences of strain-dependence, time non-linearity, and interaction with olaparib on the pharmacokinetics of AZD7648 were investigated. Direct and indirect inhibition PD models were fitted to the responses of biomarkers describing target engagement (pDNA-PK) or proximal downstream effects (pRPA32(S4/8) and γH2AX). A compartmental model accurately described AZD7648 PK inmice, with rapid absorption, dose-proportional PK across the range of doses tested,time-independent parameters and no effect of olaparib co-dosing on AZD7648 PK.The PD of proximal target engagement biomarkers were best described with anImax model with very rapid turnover (<10 minutes), which showed there was negligible delay (due to tumor distribution or pharmacology) and effectively a direct relationship between systemic PK and xenograft biomarker inhibition.Across a number of FaDu ATM KO and BT474c xenograft tumor studies, the durationof cover over IC90 correlated with efficacy in combination with olaparib orPLD, demonstrating the importance of inhibiting DNA-PK for an extended durationin each dosing period. This result was applied to define a target level andduration of PD inhibition, and, when combined with predicted human PK behaviour, a target clinical dose for AZD7648 in combination with DSB-inducing agents to inform the clinical investigation of AZD7648.
3512/ 23 - AZD7648, a potent and selective inhibitor of DNA-PK, potentiates theactivity of ionising radiation and doxorubicin in vitro and causes tumour regression in xenograft models
https://www.abstractsonline.com/pp8/#!/6812/presentation/987
April2, 2019, 8:00 AM - 12:00 PM
Abstract
DNA-dependent kinase (DNA-PK) is a nuclear serine/threonine protein kinase complex that is a key component of the non-homologous end joining (NHEJ) process. DNA-PK plays an important role inthe cellular response to DNA damage through the detection and repair of DNA double strand breaks (DSB). Cancer therapies such as ionising radiation (IR) or topoisomerase II inhibitors (doxorubicin) generate DSB which can be repaired by homologous recombination (HR) or non-homologous end-joining (NHEJ). It can therefore be hypothesised a DNA-PK inhibitor would potentiate the activity ofthese agents. We have developed a highly potent and selective inhibitor of DNA-PK, AZD7648, which inhibits IR-induced DNA-PK S2056 auto phosphoryalation with an IC50 = 92 nM in A549 non-small cell lung cancer (NSCLC) cells. AZD7648 is a potent radiosensitiser where treatment in combination with IR led to a concentration-dependent reduction of the colony survival capacity of A549 and H1299 NSCLC cells (DEF37 at 100 nM = 1.7 and 2.5, respectively). In A549 cells,AZD7648 (≥1 µM) in combination with 2Gy IR for 48 hours led to a significant accumulation of cells arrested in the G2/M of the cell cycle, a 4-fold increasein micronuclei formation, and 3-fold induction of γH2AX, pATMS1981 and 53BP1 foci formation compared with IR alone. AZD7648 was also foundto combine synergistically with doxorubicin in a panel of ovarian and triplenegative breast cancer (TNBC) cell lines in cell growth inhibition assays when applying the Loewe additivity model (synergy scores 4 - 35). In vivo the combination of AZD7648 with IR (5x 2Gy) induced tumour regression in H1299 and A549 NSCLC xenografts in a dose-dependent manner (84 and 11% regressionrespectively), while monotherapy treatment only achieved tumour growth inhibition. In these two models the increased activation by IR of three primary DNA-PK pharmacodynamic markers, pDNAPK (S2056), pRPA32 (S4/8) and γH2AX, was inhibited by AZD7648 treatment (70-90% inhibition 2 h after IR + AZD7648).Similarly, liposomal doxorubicin (2.5 mg/kg weekly) in combination with AZD7648(37.5 mg/kg bid) induced tumour regressions in the BT474c ER+ breast cancer xenograft model and in a TNBC PDX model (63% and 33% regression respectively),while monotherapy treatments only achieved tumour growth inhibition. These data confirm that DNA-PK inhibition with AZD7648 enhances the efficacy of a range ofDSB inducing agents in vitro and in vivo, providing a clear rationale for its clinical investigation.
Five Prime-CD80 Fc
A first-in-class therapeutic CD80-Fc fusion protein that augments T cell co-stimulation
https://www.abstractsonline.com/pp8/#!/6812/presentation/7591
March 31, 2019, 1:48 PM - 2:12 PM
Takeda-TAK-981 SUMOylation inhibitor
https://www.abstractsonline.com/pp8/#!/6812/presentations/TAK%20981/1
TAK-981:A first-in-class SUMOylation inhibitor in phase 1 clinical trials promotes aType I interferon response and antitumor immunity in preclinical models
https://www.abstractsonline.com/pp8/#!/6812/presentation/7593
March 31, 2019, 2:36 PM - 3:00 PM
3079 / 13 - Pharmacodynamic evaluation ofthe novel SUMOylation inhibitor TAK-981 in a mouse tumor model
https://www.abstractsonline.com/pp8/#!/6812/presentation/7517
April 2, 2019, 8:00 AM - 12:00 PM
Abstract
TAK-981 is a small molecule inhibitor ofthe SUMOylation enzyme cascade which is currently in a Phase I clinical trial(NCT03648372). TAK-981 selectively inhibits the activity of the SUMO activating enzyme, forming a covalent adduct between TAK-981 and SUMO, thereby decreasinglevels of SUMOylated proteins. A central feature of pharmacological inhibition of SUMOylation is production of type I IFNs in immune cells, promoting bothinnate and adaptive immune responses.
TAK-981 demonstrates antitumor activity,including complete regression (CR) of some tumors, in immune-competent BALB/c mice bearing syngeneic A20 lymphoma tumors. This model was utilized to investigate 1) target engagement and pathway inhibition, 2) modulation of IFN-regulated genes in tumor and blood, 3) dependence of antitumor activity on Type I IFN signaling and adaptive immunity, and 4) changes in immune cell infiltrates in tumors.
IHC analysis of tumors showed TAK-981-SUMO adduct formation and decrease of SUMOylated protein levels after a single IV
dose of 7.5 mg/kg TAK-981, as measured by assays for TAK-981-SUMO adduct andSUMO2/3 conjugates, respectively. IFN-regulated genes including CXCL10, IFIT1,and ISG15 are coordinately upregulated 4-8 hrs post-dose in tumor and in blood,as demonstrated by Nanostring, and plasma levels of IP-10 (CXCL10) increase.Single cell RNAseq experiments on dissociated tumors demonstrated upregulationof IFN-regulated genes in T cells and monocytes in the tumor microenvironment.
TAK-981-mediated antitumor activity is fully dependent on Type I IFN signaling; administration of a neutralizing antibody against the IFN alpha/beta receptor 1 (IFNAR) before dosing TAK-981 results in the loss of antitumor activity against A20. TAK-981-mediated antitumor activity is also dependent on the adaptive immune system, as demonstrated by two experiments in mice lacking T cells (BALB/c Rag2 KO mice, and mice treatedwith an anti-CD8 antibody to deplete T cells). Antitumor response was diminished in both settings, with no CRs achieved in either model. Flow cytometric analysis of immune infiltrates in A20 tumors grown in BALB/c miceindicated that TAK-981 response is accompanied by an increase in activated Tcells in the tumor microenvironment as well as increased NK cells, potentially supporting a role for both innate and adaptive immunity in the MOA.
Evaluation of pharmacodynamic biomarkers inPhase I clinical development will be informed by these preclinical studies.
BI-BI 905677 LPR5/6 Antagonist
DDT01-01 - BI 905677: A first-in-class LRP5/6 antagonist targeting Wnt-driven proliferation and immune escape
https://www.abstractsonline.com/pp8/#!/6812/presentation/7589
March 31, 2019, 1:01 PM - 1:24 PM
Abstract
Aberrant Wnt/β-catenin signalling has been shown to play a key role in tumor genesis and resistance to immunotherapy in several tumor indications. Wnt ligand-mediated signals are transduced by twodistinct receptor types, the serpentine receptor Frizzled (FZD) and the closely related single-span transmembrane proteins LRP5 and LRP6. Formation of the FZD-Wnt-LRP5/6 trimeric complex induces phosphorylation of LRP5 or LRP6 intracellular domains leading to inactivation of the β-catenin degradation complex, allowing stabilized β-catenin to enter the nucleus, bind to the TCF transcription factors, and act as a transcriptional activator of Wnt targetgenes. We have developed a first-in-class LRP5/6 antagonist, a bi-paratopic antibody comprising two modules binding to distinct epitopes of LRP5 (or LRP6).BI 905677 is a highly potent blocker of signalling induced by the Wnt family of ligands and shows anti-tumor activity in cancer models harbouring genomic alterations in upstream regulators of the Wnt pathway, such as RNF43 mutationsor RSPO fusions. Furthermore, BI 905677 in combination with an anti-PD-1 immune checkpoint inhibitor induces dendritic cell activation and T cell infiltrationin tumor tissues leading to complete responses in syngeneic tumor models. A Phase I clinical trial is underway in patients with advanced cancer to evaluate safety, tolerability, pharmacokinetic and pharmacodynamic properties, and efficacy of BI 905677 (NCT03604445).
CellCentric Ltd-p300/CBP Bromo inhibitor
A first-in-class p300/CBP bromodomain inhibitor for the treatment of prostate cancer and hematologic malignancies
https://www.abstractsonline.com/pp8/#!/6812/presentation/7592
March 31, 2019, 2:12 PM - 2:36 PM
https://www.abstractsonline.com/pp8/#!/6812/presentations/p300$_2fcbp/1
2694 - A first-in-class small-molecule modulator of the p300/CBP interactome exhibits broad efficacy in xenograft models of solid tumors and hematologic malignancies
https://www.abstractsonline.com/pp8/#!/6812/presentation/7499
April 1, 2019, 3:00 PM - 5:00 PM
Abstract
Background: Dysregulation of the cellular transcription machinery is a fundamental feature of cancer. E1A binding protein(p300) and CREB binding protein (CBP) are two closely related paralog transcription co-activators involved in the expression of oncogenic drivers incancer cells.
Methods: Small molecule ligands of the CH1/TAZ1 domain of p300/CBP were rationally designed and optimized for their anti-proliferative activity in vitro. Subsequent characterization focused on their ability to modulate downstream biological processes controlled byp300/CBP, including hormone-dependent androgen receptor signalling, the HIF-1 alpha/VEGF pathway and reactivation of p53 in HPV-positive carcinomas.
The in vivo efficacy of this novel compound class was assessed in a variety of patient and cell line derived xenograft models, and pharmacodynamic effects were investigated.
Results: Several modulators of p300/CBP exhibited anti-proliferative effects at low nanomolar concentrations in morethan 60 cancer cell lines inducing both senescence and apoptosis in a highly context dependent manner. Transcriptome analyses revealed the downregulation of various drivers of cell cycle progression.
Once daily oral administration triggered strong growth-inhibitory effects in several xenograft models up to complete tumor eradication at well tolerated doses. p300/CBP dependent biomarkers like VEGF (colon cancer) and PSA (prostate cancer) were significantly downregulated in the tumors of treated animals. In an orthotopic model of acute myeloid leukemia, the growth of primary tumors and metastasis was almost completely inhibited.
Conclusions: Reprogramming the transcriptional profile of cancer cells by modulation of p300/CBP activity by targeting the CH1/TAZ1 domain represents a novel and broadly applicable approach for the treatment of cancer. The presented data illustrate the clinical potential of this new class of therapeutics against a broad variety oftumor types, including prostate and colon cancer as well as hematological malignancies.